Influences of Maternal Vulnerability and Antidepressant Treatment during Pregnancy on the Developing Offspring

*Laura Staal and Jocelien DA Olivier*

### **Abstract**

Maternal vulnerability to adversity has long-term impact on the developing child. About 20% of the pregnant women suffer from affective disorders. Fetal exposure to maternal adversity may lead to detrimental consequences later in life. Maternal affective disorders are increasingly treated with antidepressants, especially selective serotonin reuptake inhibitors (SSRIs). However, the long-term consequences for the offspring after exposure to this medication are unclear. The interplay between maternal adversity and SSRI treatment has been under investigation and here we discuss how maternal adversity and SSRIs are able to shape offspring development. Specifically, we will discuss animal models addressing behavioral outcomes to understand how the prenatal environment influences the health of the developing child across the life span.

**Keywords:** maternal vulnerability, maternal depression, selective serotonin reuptake inhibitors, antidepressants, pregnancy, neurodevelopment

#### **1. Introduction**

Although pregnancy is often portrayed as a time of great joy, that is not the reality for all women. Depressive symptoms during pregnancy are not uncommon; in fact, 20% of women experience some depressive symptoms during any time of their pregnancy [1]. The number of women who suffer from major depression during pregnancy is estimated to be 4–8% [2, 3]. According to the DSM-5, this disorder is characterized by a depressed mood or loss of interest or pleasure in daily activities for more than 2 weeks. Depression is accompanied by impaired social, occupational, and educational functioning. Untreated antenatal depression, that is to say a depressive episode during pregnancy, may have a tremendous effect on the developing child [4].

Maternal vulnerabilities during pregnancy, such as depression, anxiety, or high stress levels due to other reasons, are associated with increased and continued activation of the hypothalamic-pituitary-adrenal (HPA) axis. The continued activation of the HPA axis in depressed patients causes an elevated stress response and increased cortisol levels [5]. About 40% of the cortisol passes through the placenta [6]. Consequently, increased cortisol levels are found in the urine and saliva of the infants of depressed mothers [7].

Fetal exposure to increased maternal stress levels impacts the developing child. For example, high levels of maternal cortisol are associated with reduced neurological development [8] and altered cortisol responses of the unborn child to a stressor [9]. Furthermore, maternal vulnerabilities such as anxiety, depression, and elevated stress levels are associated with the increased fearful temperament and negative behavioral reactivity to novelty in infants [9, 10], and delayed cognitive and neuromotor development [11, 12] that persists into adolescence [13]. In addition, antenatal depression has also been linked with disturbed sleep patterns in infants [14] and in 18 and 30 months old children [15]. Furthermore, antenatal depression has been linked to reduced fetal growth [16, 17] and altered cardiovascular responses to stress [18].

Several studies have looked into the effects of maternal vulnerability on the behavioral development of the child. For example, maternal anxiety, but not antenatal depression is linked to a difficult child temperament at the age of 4–6 months [19], an increase in behavioral and emotional problems at the age of 4 [20] and more internalizing behavior at the age of 8 [21]. Moreover, antenatal depression is associated with delayed development in 18-month-olds [22], increased externalizing behaviors and a slight decrease in IQ in 8-year-old children [21], and violent behavior during adolescence [23]. On the long-term prenatal exposure to maternal depression is associated with a higher chance of developing depression during adolescence [24, 25] and adulthood [26], or risk of developing other psychopathologies [27]. Maternal anxiety as well as maternal depression during pregnancy is correlated with child attention problems at the age of 3 and 4 [28]. Moreover, an increase in reporting symptoms of antenatal depression and anxiety positively correlated with an increase in internalizing behaviors in 4-year-olds [29]. So anxiety and depression appear to have similar but, at the same time, different effects on offspring development; however, it is difficult to discern between maternal anxiety and depression, due to common comorbidity between these mental health conditions [30].

Overall, maternal vulnerability, such as depression and anxiety, during pregnancy can negatively influence the unborn child on both physiological and behavioral levels. However, it remains difficult to discern the direct effects of antenatal depression (an aversive postnatal environment due to a depressed mother), and genetic predisposition to vulnerability on fetal and infant development. In addition, an increasing percentage of women suffering from depression and/or anxiety are treated with antidepressants, which on itself might have tremendous effects on the developing child.

#### **2. Maternal SSRI treatment and offspring development**

Pharmacological treatment of antenatal depression and/or anxiety is sometimes unavoidable. The treatment with antidepressants may relieve the symptoms of the depression of the mother and could help in reducing the impact on the unborn child. Nowadays, a considerable number of women are treated with antidepressants during pregnancy. In Europe, this concerns 2–3% of the pregnant women [16, 31], while in the U.S., the occurrence is as high as up to 13% [32, 33]. The most prescribed antidepressants are selective serotonin reuptake inhibitors (SSRIs), because of their good efficacy, few side effects, and therapeutic safety [34]. These drugs work by blocking the serotonin transporter and hereby preventing the reabsorption of the neurotransmitter serotonin into the presynaptic nerve cell. Subsequently, extracellular serotonin levels in the synaptic cleft are increased and more serotonin is available to bind the postsynaptic receptors. Although, SSRIs are considered safe for antenatal use [35], it has been reported that the use of SSRIs during pregnancy may negatively influence the development of the unborn child. SSRIs can cross the

**69**

antenatal depression [4].

*Influences of Maternal Vulnerability and Antidepressant Treatment during Pregnancy…*

placenta and are found in the amniotic fluid [36, 37], affecting therefore not only the mother but also the developing child. This is of extra concern as serotonin plays a key role in embryonal development. During the development of the fetal brain, serotonin acts as a neurotrophic factor, regulating cell division, differentiation, migration, growth cone elongation, dendritic pruning, myelination, and synaptogenesis [38]. In fact, serotonin receptors and serotonergic metabolic enzymes are expressed before serotonin-producing neurons are present in the brain [39]. Thus, changes in the serotonin levels during neurodevelopment, for instance, by the administration of SSRIs during pregnancy, potentially affect a number of processes

Indeed, literature shows a number of side effects in the offspring due to prenatal SSRI exposure. First of all, SSRI exposure during pregnancy has been associated with attenuated basal cortisol levels in neonates [40, 41], and differential cortisol levels in 3-month-old infants in response to a stressor [42]. Also, the neonatal heart rate response to an acute noxious event is attenuated [43]. Furthermore, several behavioral changes have been reported, such as increased internalizing behaviors, such as depression, anxiety, and social withdrawal during childhood [44, 45], increased externalizing behaviors in 4-year-old children [46], and disrupted sleep patterns in newborn [47]. In addition, SSRIs reduce utero-placental blood flow, a mechanism thought to be involved with hypertension in preeclampsia and gesta-

Recently, there has been much interest in the link between antenatal SSRI treatment and the development of autism spectrum disorders (ASDs) in the child. ASD is a neurodevelopmental condition characterized by difficulties in social communication and unusually restricted, repetitive behavior and interests. The available literature shows an association between the prenatal use of SSRIs and the increased risk of ASDs in the child [50–54]. It is theorized that this is facilitated by an increase in serotonergic activity during brain development [55]. Several studies found abnormal placental histology to be associated with autism diagnosis [56, 57]. Moreover, autistic patients have elevated blood platelet serotonin levels [58, 59]. Taken together, these results imply the serotonergic influences on maternal-fetal interaction, although the exact mechanisms

A possible route for passing adverse intra-uterine effects to the fetus is via epigenetic regulation. For example, increased maternal depressive mood during pregnancy is associated with reduced methylation of the promotor of the gene coding the serotonin transporter (SERT) in both mothers and newborns [60]. These results suggest increased SERT mRNA levels and subsequently modified serotonin levels, contributing to increased vulnerability later in life [61]. St-Pierre and colleagues therefore conclude that all parameters that can alter serotonin homeostasis during early development could lead to structural and functional changes in fetal development and brain circuits [62], which could subsequently result in a predispo-

Thus, several studies have shown an increased risk for developing the child both during antenatal depression and after prenatal SSRI exposure. However, it is difficult to discern between the effects of the SSRIs and the effects of the depression itself, as healthy mothers do not administer antidepressants. For example, meta-analyses show that the risk found for ASD in the offspring after prenatal SSRI exposure is decreased after correcting for maternal mental illness [63]. Thus, the effects of SSRIs mentioned could be solely due to the administration of the SSRIs, or alternatively, the SSRIs are only partially effective and therefore do not eliminate all the adverse effects of the depression, thereby adding up to the adverse effects of

*DOI: http://dx.doi.org/10.5772/intechopen.83761*

in the offspring.

tional diabetes [48, 49].

remain elusive.

sition to psychopathology in adulthood.

#### *Influences of Maternal Vulnerability and Antidepressant Treatment during Pregnancy… DOI: http://dx.doi.org/10.5772/intechopen.83761*

placenta and are found in the amniotic fluid [36, 37], affecting therefore not only the mother but also the developing child. This is of extra concern as serotonin plays a key role in embryonal development. During the development of the fetal brain, serotonin acts as a neurotrophic factor, regulating cell division, differentiation, migration, growth cone elongation, dendritic pruning, myelination, and synaptogenesis [38]. In fact, serotonin receptors and serotonergic metabolic enzymes are expressed before serotonin-producing neurons are present in the brain [39]. Thus, changes in the serotonin levels during neurodevelopment, for instance, by the administration of SSRIs during pregnancy, potentially affect a number of processes in the offspring.

Indeed, literature shows a number of side effects in the offspring due to prenatal SSRI exposure. First of all, SSRI exposure during pregnancy has been associated with attenuated basal cortisol levels in neonates [40, 41], and differential cortisol levels in 3-month-old infants in response to a stressor [42]. Also, the neonatal heart rate response to an acute noxious event is attenuated [43]. Furthermore, several behavioral changes have been reported, such as increased internalizing behaviors, such as depression, anxiety, and social withdrawal during childhood [44, 45], increased externalizing behaviors in 4-year-old children [46], and disrupted sleep patterns in newborn [47]. In addition, SSRIs reduce utero-placental blood flow, a mechanism thought to be involved with hypertension in preeclampsia and gestational diabetes [48, 49].

Recently, there has been much interest in the link between antenatal SSRI treatment and the development of autism spectrum disorders (ASDs) in the child. ASD is a neurodevelopmental condition characterized by difficulties in social communication and unusually restricted, repetitive behavior and interests. The available literature shows an association between the prenatal use of SSRIs and the increased risk of ASDs in the child [50–54]. It is theorized that this is facilitated by an increase in serotonergic activity during brain development [55]. Several studies found abnormal placental histology to be associated with autism diagnosis [56, 57]. Moreover, autistic patients have elevated blood platelet serotonin levels [58, 59]. Taken together, these results imply the serotonergic influences on maternal-fetal interaction, although the exact mechanisms remain elusive.

A possible route for passing adverse intra-uterine effects to the fetus is via epigenetic regulation. For example, increased maternal depressive mood during pregnancy is associated with reduced methylation of the promotor of the gene coding the serotonin transporter (SERT) in both mothers and newborns [60]. These results suggest increased SERT mRNA levels and subsequently modified serotonin levels, contributing to increased vulnerability later in life [61]. St-Pierre and colleagues therefore conclude that all parameters that can alter serotonin homeostasis during early development could lead to structural and functional changes in fetal development and brain circuits [62], which could subsequently result in a predisposition to psychopathology in adulthood.

Thus, several studies have shown an increased risk for developing the child both during antenatal depression and after prenatal SSRI exposure. However, it is difficult to discern between the effects of the SSRIs and the effects of the depression itself, as healthy mothers do not administer antidepressants. For example, meta-analyses show that the risk found for ASD in the offspring after prenatal SSRI exposure is decreased after correcting for maternal mental illness [63]. Thus, the effects of SSRIs mentioned could be solely due to the administration of the SSRIs, or alternatively, the SSRIs are only partially effective and therefore do not eliminate all the adverse effects of the depression, thereby adding up to the adverse effects of antenatal depression [4].

*Antidepressants - Preclinical, Clinical and Translational Aspects*

Fetal exposure to increased maternal stress levels impacts the developing child. For example, high levels of maternal cortisol are associated with reduced neurological development [8] and altered cortisol responses of the unborn child to a stressor [9]. Furthermore, maternal vulnerabilities such as anxiety, depression, and elevated stress levels are associated with the increased fearful temperament and negative behavioral reactivity to novelty in infants [9, 10], and delayed cognitive and neuromotor development [11, 12] that persists into adolescence [13]. In addition, antenatal depression has also been linked with disturbed sleep patterns in infants [14] and in 18 and 30 months old children [15]. Furthermore, antenatal depression has been linked to reduced fetal growth [16, 17] and altered cardiovascular responses to stress [18]. Several studies have looked into the effects of maternal vulnerability on the behavioral development of the child. For example, maternal anxiety, but not antenatal depression is linked to a difficult child temperament at the age of 4–6 months [19], an increase in behavioral and emotional problems at the age of 4 [20] and more internalizing behavior at the age of 8 [21]. Moreover, antenatal depression is associated with delayed development in 18-month-olds [22], increased externalizing behaviors and a slight decrease in IQ in 8-year-old children [21], and violent behavior during adolescence [23]. On the long-term prenatal exposure to maternal depression is associated with a higher chance of developing depression during adolescence [24, 25] and adulthood [26], or risk of developing other psychopathologies [27]. Maternal anxiety as well as maternal depression during pregnancy is correlated with child attention problems at the age of 3 and 4 [28]. Moreover, an increase in reporting symptoms of antenatal depression and anxiety positively correlated with an increase in internalizing behaviors in 4-year-olds [29]. So anxiety and depression appear to have similar but, at the same time, different effects on offspring development; however, it is difficult to discern between maternal anxiety and depression,

due to common comorbidity between these mental health conditions [30].

**2. Maternal SSRI treatment and offspring development**

Overall, maternal vulnerability, such as depression and anxiety, during pregnancy can negatively influence the unborn child on both physiological and behavioral levels. However, it remains difficult to discern the direct effects of antenatal depression (an aversive postnatal environment due to a depressed mother), and genetic predisposition to vulnerability on fetal and infant development. In addition, an increasing percentage of women suffering from depression and/or anxiety are treated with antidepressants, which on itself might have tremendous effects on the

Pharmacological treatment of antenatal depression and/or anxiety is sometimes

unavoidable. The treatment with antidepressants may relieve the symptoms of the depression of the mother and could help in reducing the impact on the unborn child. Nowadays, a considerable number of women are treated with antidepressants during pregnancy. In Europe, this concerns 2–3% of the pregnant women [16, 31], while in the U.S., the occurrence is as high as up to 13% [32, 33]. The most prescribed antidepressants are selective serotonin reuptake inhibitors (SSRIs), because of their good efficacy, few side effects, and therapeutic safety [34]. These drugs work by blocking the serotonin transporter and hereby preventing the reabsorption of the neurotransmitter serotonin into the presynaptic nerve cell. Subsequently, extracellular serotonin levels in the synaptic cleft are increased and more serotonin is available to bind the postsynaptic receptors. Although, SSRIs are considered safe for antenatal use [35], it has been reported that the use of SSRIs during pregnancy may negatively influence the development of the unborn child. SSRIs can cross the

**68**

developing child.

#### **3. Preclinical studies: perinatal SSRI exposure**

In humans, it is difficult, if not impossible, to discern the effects of the SSRI and the depression itself on fetal development. It is not ethical to study the effects of SSRIs in healthy pregnant women. In addition, it is impossible to study gene expression and epigenetic changes in the fetal brain as a result of prenatal SSRI exposure. Due to these limitations of human research, researchers often use animal models, specifically rodents, to get a more profound insight into the mechanisms underlying the observations seen in human studies.

It should be noted that the timing of brain development is different in humans compared to rodents. A rodent brain at postnatal day 7–10 is considered to be the rough equivalent of a newborn human infant [64]. Thus, to mimic SSRI exposure during the entire pregnancy in humans, rodents should be exposed both pre- and postnatally. In addition, it is known that SSRIs are also found in breast milk [65], again underlining the need to research both the effects of pre- and postnatal SSRI exposure. For exposure to SSRIs around these time points, we will use the term perinatal SSRI exposure; when timing of the SSRI exposure is of particular importance, we will distinguish between pre- and postnatal exposure to SSRIs.

#### **3.1 Social behavior**

As serotonin is a key regulator of social responses and prenatal SSRI exposure is being linked to ASDs, which are characterized by impaired social behavior [54], this behavioral parameter is often addressed in researching the effects of prenatal SSRI exposure in animals.

Social play at juvenile age is an essential behavior in rodents for the development of the necessary social, cognitive, emotional, and physical skills [66]. SSRIs are well described in literature as reducing social play behavior in young rats when prenatally [67] or postnatally [68–71] administered. These effects of SSRIs seem sex-mediated, as males are more affected than females [70], or females are not even affected at all [71]. This is interesting because this is analogous to the situation, where men are 3–4 times more likely to get diagnosed with ASDs compared to women [72]. In spite of that, not all studies found similar results. In a recent study [73], social play behavior was unaltered after prenatal SSRI exposure. However, in the latter study, social play was assessed with a familiar play partner (littermate), while other studies use a novel conspecific.

Findings on the effects of prenatal SSRI exposure on social behavior at adult age are more conflicting. Olivier and colleagues [67] found reduced social exploration in adult male rats after prenatal SSRI exposure. While another study found that 4 days of postnatal treatment with SSRIs led to increased sniffing, contact with, and total social interaction with a novel conspecific in males [74]. On top of that, other studies found no effect of prenatal SSRI exposure on social exploration in both males and females [75, 76]. In general, studies on the exposure of SSRIs during early development on adult social interaction are unconvincing. Studies on social motivation on the other hand, measured as the preference of a rodent to spend time with a novel conspecific over interaction with an object, appear to be more in line. Decreased social motivation is found in both males and females, when postnatally exposed to SSRIs [69–71, 77]. On the other hand, prenatal exposure to SSRIs led to an increase in motivation to interact with a conspecific in mice [75]. Thus, while literature on the effects of perinatal SSRI exposure on social behavior during adult is still limited, both timing of the exposure and sex are important factors in the subsequent social development.

Another form of social interaction under the influence of the neurotransmitter serotonin is aggression [78]. Indeed, during both childhood and adulthood, SSRIs are successfully used to reduce aggressive and violent behavior in certain mental disorders

**71**

**3.2 Affective behavior**

as major depressive disorder and anxiety disorders.

this and the role of timing and sex, more researches have to be done.

*Influences of Maternal Vulnerability and Antidepressant Treatment during Pregnancy…*

[79, 80]. Perinatal exposure to SSRIs, on the other hand, leads to increased externalizing behavior, such as aggression, in children [46]. In rodents, the effects of perinatal SSRI exposure on aggressive behavior are conflicting. Several studies show an increase in male, but not female aggressive behavior [73, 75, 76, 81], while other studies show reduced aggressive behavior in male rodents perinatally exposed to SSRIs [82, 83]. Serotonin is known to be involved in the regulation of maternal care [84]. Thus, perinatal SSRI exposure can be expected to alter maternal caregiving behavior of both the SSRI-treated mother and her female offspring, when they are mothers later in life. Typical maternal behaviors include nest building, gathering the young into the nest, maternal licking, and nursing the pups. Studies on the effect of direct SSRI exposure found an increase in these behaviors [85, 86], or no effect at all [87]. So far, only one study has been performed on the effects of prenatal exposure on maternal care later in life, and interestingly here, they found a reduction in maternal caregiving behaviors [75]. This suggests that direct changes in serotonin levels, such as an increase in extracellular serotonin levels during SSRI treatment and changes in serotonin levels during development differentially alter the quality of maternal care. Another role for serotonin is its signaling in sexual development, on both the brain and at a behavioral level [88]. In addition, chronic SSRI treatment may result in sexual dysfunction [89]. Not much is known on the effect of perinatal SSRI exposure on the sexual behavior of these children later in life; however, several studies have been performed in rodents. The effect of perinatal SSRI exposure depends on the timing of treatment. When postnatally administered, male sexual behavior later in life is reduced [70, 90–93]. In contrast when the SSRI is prenatally, or both prenatally and postnatally, administered, there is no effect on sexual behavior of male rodents [94, 95]. Interestingly, there appears to be an opposite effect in female offspring, where postnatal SSRI exposure leads to an increase in sexual behaviors [75, 96]. Thus, apart from the effect of timing, sex of the offspring also differentially alters the effect of perinatal SSRI exposure on reproductive behavior.

It has long been established that serotonin is involved in affective disorders [97]. Affective disorders, also called mood disorders, include psychiatric disorders such

A large body of preclinical research has shown the relationship between perinatal SSRI exposure and anxiety. Although there are some studies finding no effects, several studies did find an increase in anxiety-like behavior and/or less explorative behavior in an open field test, when rodents are perinatally exposed to SSRIs [67, 83, 98–104]. An increase in anxiety-like behavior in the elevated plus maze and the novelty-suppressed feeding test are also found [67, 98, 99, 105]. Nevertheless, there are also studies that did not find effects at all [87, 91, 106–111], and two studies even found a decrease in behaviors related to anxiety [92, 112]. Even though results differ among studies, these differences are not clearly linked to sex of the offspring or timing of the SSRI exposure. So even though there appears to be a clear link between perinatal SSRI exposure and anxiety later in life, to get a more profound insight into the mechanisms behind

It is difficult to determine if a rodent is depressed, moreover, to determine if it is even possible for rodents to experience depression. However, rodents can show behavior characteristics of the behaviors, and humans show during episodes of major depression. Such behaviors encompass despair and anhedonia [113]. To measure behavioral despair in rodents, the forced swim test is usually performed [114]. In this test, the animal is placed in an unescapable container filled with water, forcing the rodent to swim. After making efforts to escape the animal may

*DOI: http://dx.doi.org/10.5772/intechopen.83761*

#### *Influences of Maternal Vulnerability and Antidepressant Treatment during Pregnancy… DOI: http://dx.doi.org/10.5772/intechopen.83761*

[79, 80]. Perinatal exposure to SSRIs, on the other hand, leads to increased externalizing behavior, such as aggression, in children [46]. In rodents, the effects of perinatal SSRI exposure on aggressive behavior are conflicting. Several studies show an increase in male, but not female aggressive behavior [73, 75, 76, 81], while other studies show reduced aggressive behavior in male rodents perinatally exposed to SSRIs [82, 83].

Serotonin is known to be involved in the regulation of maternal care [84]. Thus, perinatal SSRI exposure can be expected to alter maternal caregiving behavior of both the SSRI-treated mother and her female offspring, when they are mothers later in life. Typical maternal behaviors include nest building, gathering the young into the nest, maternal licking, and nursing the pups. Studies on the effect of direct SSRI exposure found an increase in these behaviors [85, 86], or no effect at all [87]. So far, only one study has been performed on the effects of prenatal exposure on maternal care later in life, and interestingly here, they found a reduction in maternal caregiving behaviors [75]. This suggests that direct changes in serotonin levels, such as an increase in extracellular serotonin levels during SSRI treatment and changes in serotonin levels during development differentially alter the quality of maternal care.

Another role for serotonin is its signaling in sexual development, on both the brain and at a behavioral level [88]. In addition, chronic SSRI treatment may result in sexual dysfunction [89]. Not much is known on the effect of perinatal SSRI exposure on the sexual behavior of these children later in life; however, several studies have been performed in rodents. The effect of perinatal SSRI exposure depends on the timing of treatment. When postnatally administered, male sexual behavior later in life is reduced [70, 90–93]. In contrast when the SSRI is prenatally, or both prenatally and postnatally, administered, there is no effect on sexual behavior of male rodents [94, 95]. Interestingly, there appears to be an opposite effect in female offspring, where postnatal SSRI exposure leads to an increase in sexual behaviors [75, 96]. Thus, apart from the effect of timing, sex of the offspring also differentially alters the effect of perinatal SSRI exposure on reproductive behavior.

#### **3.2 Affective behavior**

*Antidepressants - Preclinical, Clinical and Translational Aspects*

**3. Preclinical studies: perinatal SSRI exposure**

the observations seen in human studies.

**3.1 Social behavior**

exposure in animals.

In humans, it is difficult, if not impossible, to discern the effects of the SSRI and the depression itself on fetal development. It is not ethical to study the effects of SSRIs in healthy pregnant women. In addition, it is impossible to study gene expression and epigenetic changes in the fetal brain as a result of prenatal SSRI exposure. Due to these limitations of human research, researchers often use animal models, specifically rodents, to get a more profound insight into the mechanisms underlying

It should be noted that the timing of brain development is different in humans compared to rodents. A rodent brain at postnatal day 7–10 is considered to be the rough equivalent of a newborn human infant [64]. Thus, to mimic SSRI exposure during the entire pregnancy in humans, rodents should be exposed both pre- and postnatally. In addition, it is known that SSRIs are also found in breast milk [65], again underlining the need to research both the effects of pre- and postnatal SSRI exposure. For exposure to SSRIs around these time points, we will use the term perinatal SSRI exposure; when timing of the SSRI exposure is of particular importance,

As serotonin is a key regulator of social responses and prenatal SSRI exposure is being linked to ASDs, which are characterized by impaired social behavior [54], this behavioral parameter is often addressed in researching the effects of prenatal SSRI

Social play at juvenile age is an essential behavior in rodents for the development of the necessary social, cognitive, emotional, and physical skills [66]. SSRIs are well described in literature as reducing social play behavior in young rats when prenatally [67] or postnatally [68–71] administered. These effects of SSRIs seem sex-mediated, as males are more affected than females [70], or females are not even affected at all [71]. This is interesting because this is analogous to the situation, where men are 3–4 times more likely to get diagnosed with ASDs compared to women [72]. In spite of that, not all studies found similar results. In a recent study [73], social play behavior was unaltered after prenatal SSRI exposure. However, in the latter study, social play was assessed with a familiar play partner (littermate), while other studies use a novel conspecific. Findings on the effects of prenatal SSRI exposure on social behavior at adult age are more conflicting. Olivier and colleagues [67] found reduced social exploration in adult male rats after prenatal SSRI exposure. While another study found that 4 days of postnatal treatment with SSRIs led to increased sniffing, contact with, and total social interaction with a novel conspecific in males [74]. On top of that, other studies found no effect of prenatal SSRI exposure on social exploration in both males and females [75, 76]. In general, studies on the exposure of SSRIs during early development on adult social interaction are unconvincing. Studies on social motivation on the other hand, measured as the preference of a rodent to spend time with a novel conspecific over interaction with an object, appear to be more in line. Decreased social motivation is found in both males and females, when postnatally exposed to SSRIs [69–71, 77]. On the other hand, prenatal exposure to SSRIs led to an increase in motivation to interact with a conspecific in mice [75]. Thus, while literature on the effects of perinatal SSRI exposure on social behavior during adult is still limited, both timing of the exposure

we will distinguish between pre- and postnatal exposure to SSRIs.

and sex are important factors in the subsequent social development.

Another form of social interaction under the influence of the neurotransmitter serotonin is aggression [78]. Indeed, during both childhood and adulthood, SSRIs are successfully used to reduce aggressive and violent behavior in certain mental disorders

**70**

It has long been established that serotonin is involved in affective disorders [97]. Affective disorders, also called mood disorders, include psychiatric disorders such as major depressive disorder and anxiety disorders.

A large body of preclinical research has shown the relationship between perinatal SSRI exposure and anxiety. Although there are some studies finding no effects, several studies did find an increase in anxiety-like behavior and/or less explorative behavior in an open field test, when rodents are perinatally exposed to SSRIs [67, 83, 98–104]. An increase in anxiety-like behavior in the elevated plus maze and the novelty-suppressed feeding test are also found [67, 98, 99, 105]. Nevertheless, there are also studies that did not find effects at all [87, 91, 106–111], and two studies even found a decrease in behaviors related to anxiety [92, 112]. Even though results differ among studies, these differences are not clearly linked to sex of the offspring or timing of the SSRI exposure. So even though there appears to be a clear link between perinatal SSRI exposure and anxiety later in life, to get a more profound insight into the mechanisms behind this and the role of timing and sex, more researches have to be done.

It is difficult to determine if a rodent is depressed, moreover, to determine if it is even possible for rodents to experience depression. However, rodents can show behavior characteristics of the behaviors, and humans show during episodes of major depression. Such behaviors encompass despair and anhedonia [113]. To measure behavioral despair in rodents, the forced swim test is usually performed [114]. In this test, the animal is placed in an unescapable container filled with water, forcing the rodent to swim. After making efforts to escape the animal may

eventually stop his efforts and become immobile. The amount of time spent immobile is used as a measure of helplessness and behavioral despair. As reviewed [115], many, but not all, studies performing the forced swim test after perinatal SSRI exposure found an increase in immobility [83, 99, 100, 105, 106, 109, 110, 116–121]. Three studies did not find an effect [67, 87, 111], and three studies even found a decrease in immobility [103, 112, 122]. The reviewers propose that these differences may be due to strain effects, some strains could be more susceptible to early life SSRI exposure, while others are resistant. In addition, they point out that the effect of perinatal SSRI exposure is greater, when the animals are exposed during early postnatal period rather than the prenatal period.

Anhedonia is another behavior often assessed as a measure for depression. Anhedonia is the inability or lack of motivation to experience pleasure from rewarding activities and is measured in rodents with the sucrose preference test [123]. In this test, two drinking bottles are placed in the rodent's home cage. One is filled with water and the other with a sucrose solution. Preference for the sucrose solution is considered as the typical hedonic behavior, and lack of bias toward the sucrose water is characterized as a sign of anhedonia. It appears that only postnatal SSRI exposure increases anhedonia later in life [124], as opposed to prenatal exposure [67, 125]. This once more emphasizes that the moment of exposure is an important factor in assessing the effects of perinatal SSRI exposure.

Thus, not only sex of the offspring, but also the timing of the SSRI exposure appears to play an important role in behavioral development. However, all aforementioned studies are performed in offspring from healthy mothers. In practice, pregnant women are usually treated with SSRIs when they are suffering from anxiety and/or depression. It is likely that both maternal factors and the treatment with SSRIs affect serotonin functioning in the embryo and infant. The interplay of these two factors might shape the development of the fetus in a different way than antenatal depression or prenatal SSRI exposure on its own. Thus, to make a more valid translational step to the human situation, animal models of maternal vulnerability have to be used.

#### **4. Preclinical studies: maternal vulnerability and perinatal SSRI exposure**

To induce maternal vulnerability in healthy rodents, researchers often use the early life stress model (ELS). Maternal separation is one of the manipulations often used to create ELS; in this procedure, the offspring is taken away from the mother for few hours during the day, and this happens daily during a period of few early postnatal weeks. This procedure leads to a long-term and intergenerational increase in anxiety and depressive-like behaviors [126–131]. Female offspring exposed to ELS and showing an increase in anxiety and depressive-live behaviors can be used as a model of maternal vulnerability later in life. Little is known about the interaction of such maternal vulnerability and treatment with SSRIs during pregnancy.

#### **4.1 Social behavior**

So far, only two studies have been looking into the combined effects of maternal vulnerability and perinatal SSRI exposure on social play behavior and social interaction of the offspring later in life. In 2017, Gemmel and colleagues [73] showed that the reduction in social play behavior in juveniles due to maternal vulnerability is prevented by perinatal SSRI treatment regardless of the sex of the offspring. This suggests a rescuing effect of SSRIs on social behavior in offspring of stressed mothers. However, social aggressive play was increased in adolescent offspring exposed

**73**

*Influences of Maternal Vulnerability and Antidepressant Treatment during Pregnancy…*

did not have any effect on the development of sexual behavior.

to perinatal fluoxetine and maternal vulnerability in both sexes. In addition, time grooming a novel conspecific was decreased in males only. In a later study, Gemmel and colleagues [132] did not find such an interaction effect on social behavior in adult offspring. Even though, maternal vulnerability itself decreased social investigation in adult males while perinatal SSRI exposure increased social investigation in adult females and increased social play in adult males. Thus, normalization, by SSRIs, of altered social play and social interaction, due to maternal vulnerability might only be short-lived as it does not persist into adulthood. With regard to aggression, however, long-term protective effects of SSRIs are found [81]. In this study, aggressive behavior was decreased as a result of maternal vulnerability, which was normalized when perinatal SSRI exposure was included in the treatment. One study has looked into the combined effect of SSRI exposure and maternal vulnerability on offspring sexual development [133]. Perinatal SSRI exposure reduced sexual behavior in male offspring, while interestingly maternal vulnerability alone or the combination of maternal vulnerability and perinatal SSRI exposure

So, even though SSRI treatment of vulnerable mothers appears to have protective effects on offspring social development, these findings are not consistent over all types of behavior and differ with the moment of assessment of the offspring.

Affective behaviors of the offspring such as anxiety and depression-like behaviors have also been studied after the offspring was exposed to a combination of maternal vulnerability and perinatal SSRI exposure. One study [134] shows that the increase in anxiety due to maternal vulnerability can be reversed by the postnatal administration of SSRIs. When prenatally administered, such a rescuing effect is not found [87]; however, the effect of maternal vulnerability was limited and was only found in males in this study. Two studies assessed depressive-like behavior after perinatal exposure to both maternal vulnerability and SSRIs. Both studies found that SSRIs normalize the increase in immobility in the forced swim test due to maternal vulnerability [87, 135]. Thus so far, the effect maternal vulnerability has on anxiety and depressive-like symptoms in the offspring later in life appear to be reversed by SSRIs.

Thus, children from mothers who suffer from anxiety or major depression during their pregnancy are at risk of developing several psychopathologies later in life. Moreover, treatment with SSRIs during pregnancy can also lead to long-term consequences for the children. However, it is difficult to determine if these effects are due to the SSRI treatment, maternal vulnerability, or a combination of both. Preclinical research in rodents shows that perinatal SSRI exposure on itself leads to alterations in social behavior later in life. Specifically, social play in juveniles, sexual behavior, maternal care in females, and aggression in males are influenced. Affective behaviors are also influenced, and both anxiety and depressive-like behaviors are increased due to perinatal SSRI exposure. Both the moments of SSRI exposure, pre- or postnatal, and sex of the offspring appear to be important factors in the development of social and affective behaviors after perinatal SSRI treatment. Recently, researchers have started to look into the combined effects of maternal vulnerability and perinatal SSRI exposure in preclinical studies to make a more valid translational step to the human situation. Even though only a few studies have been done so far, it seems that, at least some, developmental alterations on offspring

*DOI: http://dx.doi.org/10.5772/intechopen.83761*

**4.2 Affective behavior**

**5. Conclusion**

*Influences of Maternal Vulnerability and Antidepressant Treatment during Pregnancy… DOI: http://dx.doi.org/10.5772/intechopen.83761*

to perinatal fluoxetine and maternal vulnerability in both sexes. In addition, time grooming a novel conspecific was decreased in males only. In a later study, Gemmel and colleagues [132] did not find such an interaction effect on social behavior in adult offspring. Even though, maternal vulnerability itself decreased social investigation in adult males while perinatal SSRI exposure increased social investigation in adult females and increased social play in adult males. Thus, normalization, by SSRIs, of altered social play and social interaction, due to maternal vulnerability might only be short-lived as it does not persist into adulthood. With regard to aggression, however, long-term protective effects of SSRIs are found [81]. In this study, aggressive behavior was decreased as a result of maternal vulnerability, which was normalized when perinatal SSRI exposure was included in the treatment.

One study has looked into the combined effect of SSRI exposure and maternal vulnerability on offspring sexual development [133]. Perinatal SSRI exposure reduced sexual behavior in male offspring, while interestingly maternal vulnerability alone or the combination of maternal vulnerability and perinatal SSRI exposure did not have any effect on the development of sexual behavior.

So, even though SSRI treatment of vulnerable mothers appears to have protective effects on offspring social development, these findings are not consistent over all types of behavior and differ with the moment of assessment of the offspring.

#### **4.2 Affective behavior**

*Antidepressants - Preclinical, Clinical and Translational Aspects*

postnatal period rather than the prenatal period.

eventually stop his efforts and become immobile. The amount of time spent immobile is used as a measure of helplessness and behavioral despair. As reviewed [115], many, but not all, studies performing the forced swim test after perinatal SSRI exposure found an increase in immobility [83, 99, 100, 105, 106, 109, 110, 116–121]. Three studies did not find an effect [67, 87, 111], and three studies even found a decrease in immobility [103, 112, 122]. The reviewers propose that these differences may be due to strain effects, some strains could be more susceptible to early life SSRI exposure, while others are resistant. In addition, they point out that the effect of perinatal SSRI exposure is greater, when the animals are exposed during early

Anhedonia is another behavior often assessed as a measure for depression. Anhedonia is the inability or lack of motivation to experience pleasure from rewarding activities and is measured in rodents with the sucrose preference test [123]. In this test, two drinking bottles are placed in the rodent's home cage. One is filled with water and the other with a sucrose solution. Preference for the sucrose solution is considered as the typical hedonic behavior, and lack of bias toward the sucrose water is characterized as a sign of anhedonia. It appears that only postnatal SSRI exposure increases anhedonia later in life [124], as opposed to prenatal exposure [67, 125]. This once more emphasizes that the moment of exposure is an

Thus, not only sex of the offspring, but also the timing of the SSRI exposure appears to play an important role in behavioral development. However, all aforementioned studies are performed in offspring from healthy mothers. In practice, pregnant women are usually treated with SSRIs when they are suffering from anxiety and/or depression. It is likely that both maternal factors and the treatment with SSRIs affect serotonin functioning in the embryo and infant. The interplay of these two factors might shape the development of the fetus in a different way than antenatal depression or prenatal SSRI exposure on its own. Thus, to make a more valid translational step to the human situation, animal models of maternal vulnerability have to be used.

**4. Preclinical studies: maternal vulnerability and perinatal SSRI** 

To induce maternal vulnerability in healthy rodents, researchers often use the early life stress model (ELS). Maternal separation is one of the manipulations often used to create ELS; in this procedure, the offspring is taken away from the mother for few hours during the day, and this happens daily during a period of few early postnatal weeks. This procedure leads to a long-term and intergenerational increase in anxiety and depressive-like behaviors [126–131]. Female offspring exposed to ELS and showing an increase in anxiety and depressive-live behaviors can be used as a model of maternal vulnerability later in life. Little is known about the interaction of such maternal vulnerability and treatment with SSRIs during pregnancy.

So far, only two studies have been looking into the combined effects of maternal vulnerability and perinatal SSRI exposure on social play behavior and social interaction of the offspring later in life. In 2017, Gemmel and colleagues [73] showed that the reduction in social play behavior in juveniles due to maternal vulnerability is prevented by perinatal SSRI treatment regardless of the sex of the offspring. This suggests a rescuing effect of SSRIs on social behavior in offspring of stressed mothers. However, social aggressive play was increased in adolescent offspring exposed

important factor in assessing the effects of perinatal SSRI exposure.

**72**

**exposure**

**4.1 Social behavior**

Affective behaviors of the offspring such as anxiety and depression-like behaviors have also been studied after the offspring was exposed to a combination of maternal vulnerability and perinatal SSRI exposure. One study [134] shows that the increase in anxiety due to maternal vulnerability can be reversed by the postnatal administration of SSRIs. When prenatally administered, such a rescuing effect is not found [87]; however, the effect of maternal vulnerability was limited and was only found in males in this study. Two studies assessed depressive-like behavior after perinatal exposure to both maternal vulnerability and SSRIs. Both studies found that SSRIs normalize the increase in immobility in the forced swim test due to maternal vulnerability [87, 135]. Thus so far, the effect maternal vulnerability has on anxiety and depressive-like symptoms in the offspring later in life appear to be reversed by SSRIs.

#### **5. Conclusion**

Thus, children from mothers who suffer from anxiety or major depression during their pregnancy are at risk of developing several psychopathologies later in life. Moreover, treatment with SSRIs during pregnancy can also lead to long-term consequences for the children. However, it is difficult to determine if these effects are due to the SSRI treatment, maternal vulnerability, or a combination of both. Preclinical research in rodents shows that perinatal SSRI exposure on itself leads to alterations in social behavior later in life. Specifically, social play in juveniles, sexual behavior, maternal care in females, and aggression in males are influenced. Affective behaviors are also influenced, and both anxiety and depressive-like behaviors are increased due to perinatal SSRI exposure. Both the moments of SSRI exposure, pre- or postnatal, and sex of the offspring appear to be important factors in the development of social and affective behaviors after perinatal SSRI treatment.

Recently, researchers have started to look into the combined effects of maternal vulnerability and perinatal SSRI exposure in preclinical studies to make a more valid translational step to the human situation. Even though only a few studies have been done so far, it seems that, at least some, developmental alterations on offspring behavior due to maternal vulnerability can be normalized by perinatal SSRI exposure. These are interesting and promising results and further investigation into the risks and benefits of SSRI use during pregnancy in appropriate animal models are necessary to help depressed women in their decision to use SSRIs during pregnancy.

### **Conflict of interest**

The authors declare that there is no conflict of interest.

### **Author details**

Laura Staal and Jocelien DA Olivier\* Neurobiology, Groningen Institute for Evolutionary Life Sciences, Groningen, The Netherlands

\*Address all correspondence to: j.d.a.olivier@rug.nl

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**75**

*Influences of Maternal Vulnerability and Antidepressant Treatment during Pregnancy…*

Journal of Child Psychology and Psychiatry. 2011;**52**(2):119-129

Prenatal maternal anxiety and

reactivity in infancy. Infancy.

Prenatal exposure to maternal

2004;**6**(3):319-331

[10] Davis EP, Snidman N, Wadhwa PD, Glynn LM, Schetter CD, Sandman CA.

depression predict negative behavioral

[11] Davis EP, Glynn LM, Schetter CD, Hobel C, Chicz-Demet A, Sandman CA.

depression and cortisol influences infant temperament. Journal of the American Academy of Child and Adolescent Psychiatry. 2007;**46**(6):737-746

[12] Huizink AC, Robles de Medina PG, EJH M, GHA V, Buitelaar JK. Stress during pregnancy is associatedwith developmental outcome in infancy. Journal of Child Psychology and Psychiatry. 2003;**44**(6):810-818

[13] Mennes M, Stiers P, Lagae L, Van den Bergh B. Long-term cognitive sequelae of antenatal maternal anxiety: Involvement of the orbitofrontal cortex. Neuroscience and Biobehavioral

[14] Field T, Diego M, Hernandez-Reif M, Figueiredo B, Schanberg S, Kuhn C. Sleep disturbances in depressed pregnant women and their newborns. Infant Behavior & Development.

[15] O'Connor TG, Caprariello P, Blackmore ER, Gregory AM, Glover V, Fleming P. Prenatal mood disturbance predicts sleep problems in infancy and toddlerhood. Early Human Development. 2007;**83**(7):451-458

[16] El Marroun H, Jaddoe VWV, Hudziak JJ, Roza SJ, Steegers EAP, Hofman A, et al. Maternal use of selective serotonin reuptake inhibitors, fetal growth, and risk of adverse

Reviews. 2006;**30**:1078-1086

2007;**30**:127-133

*DOI: http://dx.doi.org/10.5772/intechopen.83761*

[1] Ryan D, Milis L, Misri N. Depression during pregnancy. Canadian Family Physician. 2005;**51**:1087-1093

[2] Melville JL, Gavin A, Guo Y, Fan M, Katon WJ. Depressive disorders during pregnancy: Prevalence and risk factors in a large urban sample. Obstetrics and Gynecology. 2010;**116**(5):1064-1070

[3] Kim DR, Snell JL, Ewing GC, O'Reardon J. Neuromodulation and antenatal depression: A review. Neuropsychiatric Disease and Treatment. 2015;**11**:975-982

Antenatal depression and

[4] Olivier JDA, Åkerud H, Sundström I.

[5] Field T, Diego M, Hernandez-reif M. Prenatal depression effects on the fetus and newborn: A review. Infant Behavior & Development. 2006;**29**:445-455

[7] Kaplan LA, Evans L, Monk C. Effects

modified? Early Human Development.

[8] Ellman LM, Schetter CD, Hobel CJ, Chicz-DeMet A, Glynn LM, Sandman CA. Timing of fetal exposure to stress hormones: Effects on newborn physical and neuromuscular maturation. Developmental Psychobiology.

[9] Davis EP, Glynn LM, Waffarn F, Sandman CA. Prenatal maternal stress programs infant stress regulation.

[6] Gitau R, Cameron A, Fisk NM, Glover V. Fetal exposure to maternal cortisol. Lancet. 1998;**352**:707-708

of mothers' prenatal psychiatric status and postnatal caregiving on infant biobehavioral regulation: Can prenatal programming be

2008;**84**(4):249-256

2008;**50**(3):232-241

antidepressants during pregnancy: Unraveling the complex interactions for the offspring. European Journal of Pharmacology. 2015;**753**:257-262

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*Influences of Maternal Vulnerability and Antidepressant Treatment during Pregnancy… DOI: http://dx.doi.org/10.5772/intechopen.83761*

#### **References**

*Antidepressants - Preclinical, Clinical and Translational Aspects*

The authors declare that there is no conflict of interest.

**Conflict of interest**

behavior due to maternal vulnerability can be normalized by perinatal SSRI exposure. These are interesting and promising results and further investigation into the risks and benefits of SSRI use during pregnancy in appropriate animal models are necessary to help depressed women in their decision to use SSRIs during pregnancy.

**74**

**Author details**

The Netherlands

provided the original work is properly cited.

\*Address all correspondence to: j.d.a.olivier@rug.nl

Laura Staal and Jocelien DA Olivier\*

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Neurobiology, Groningen Institute for Evolutionary Life Sciences, Groningen,

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*Antidepressants - Preclinical, Clinical and Translational Aspects*

[24] Plant DT, Pariante CM, Sharp D, Pawlby S. Maternal depression during pregnancy and offspring depression in adulthood: Role of child maltreatment. The British Journal of Psychiatry.

[25] Pawlby S, Hay DF, Waters CS, Sharp D, O'Keane V. Antenatal depression predicts depression in adolescent offspring: Prospective longitudinal community-based study. Journal of Affective Disorders.

[26] Pearson RM, Evans J, Kounali D, Lewis G, Heron J, Ramchandani PG, et al. Maternal depression during pregnancy and the postnatal period risks and possible mechanisms for offspring depression at age 18 years. JAMA Psychiatry. 2013;**70**(12):1312-1319

[27] Pawlby S, Hay D, Sharp D, Waters CS, Pariante CM. Antenatal depression and offspring psychopathology: The influence of childhood maltreatment. The British Journal of Psychiatry.

[28] Van Batenburg-Eddes T, Brion MJ, Henrichs J, Jaddoe VWV, Hofman A, Verhulst FC, et al. Parental depressive

and anxiety symptoms during pregnancy and attention problems in children: A cross-cohort consistency study. Journal of Child Psychology and

Psychiatry. 2012;**54**(5):591-600

2006;**163**:1026-1032

2014;**28**(1):25-35

[29] Misri S, Reebye P, Kendrick K, Carter D, Ryan D, Grunau RE, et al. Internalizing behaviors in 4-yearold children exposed in utero to psychotropic medications. The American Journal of Psychiatry.

[30] Glover V. Maternal depression, anxiety and stress during pregnancy and child outcome; what needs to be done. Best Practice & Research. Clinical Obstetrics & Gynaecology.

2015;**207**:213-220

2009;**113**(3):236-243

2011;**199**:106-112

birth outcomes. Archives of General Psychiatry. 2012;**69**(7):706-714

[17] Henrichs J, Schenk JJ, Roza SJ, van den Berg MP, Schmidt HG, Steegers EAP, et al. Maternal psychological distress and fetal growth trajectories: The generation R study. Psychological

Medicine. 2010;**40**:633-643

[18] Fan F, Zou Y, Tian H, Zhang Y, Zhang J, Ma X, et al. Effects of maternal anxiety and depression during pregnancy in Chinese women on children's heart rate and blood pressure response to stress. Journal of Human Hypertension. 2016;**30**:171-176

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[20] O'Connor TG, Heron J, Glover V. Antenatal anxiety predicts child behavioral/emotional problems

independently of postnatal depression. Journal of the American Academy of Child and Adolescent Psychiatry.

[21] Barker ED, Jaffee SR, Uher R, Maughan B. The contribution of prenatal and postnatal maternal anxiety and depression to child maladjustment. Depression and Anxiety. 2011;**28**(8):696-702

[22] Deave T, Heron J, Evans J, Emond A. The impact of maternal depression in pregnancy on early child development. BJOG : An International Journal of Obstetrics and Gynaecology.

[23] Hay DF, Pawlby S, Waters CS, Perra O, Sharp D. Mothers' antenatal depression and their children's antisocial

outcomes. Child Development.

2008;**115**:1043-1051

2010;**81**(1):149-165

2002;**41**(12):1470-1477

**76**

[32] Cooper WO, Willy ME, Pont SJ, Ray WA. Increasing use of antidepressants in pregnancy. American Journal of Obstetrics and Gynecology. 2007;**196**:1-5

[33] Hayes RM, Wu DP, Shelton RC, Cooper O, Dupont WD, Mitchel E, et al. Maternal antidepressant use and adverse outcomes: A cohort study of 228,876 pregnancies. American Journal of Obstetrics and Gynecology. 2012;**207**(1):49

[34] Barbey JT, Roose SP. SSRI safety in overdose. The Journal of Clinical Psychiatry. 1998;**59**:42-48

[35] Gentile S. The safety of newer antidepressantsin pregnancy and breastfeeding. Drug Safety. 2005;**28**(2):137-152

[36] Hostetter A, Stowe ZN, Strader JR, McLaughlin E, Llewellyn A. Dose of selective serotonin uptake inhibitors across pregnancy: Clinical implications. Depression and Anxiety. 2000;**11**(2):51-57

[37] Loughhead AM, Fisher AD, Newport DJ, Ritchie JC, Owens MJ, CL DV, et al. Antidepressants in amniotic fluid: Another route of fetal exposure. The American Journal of Psychiatry. 2006;**163**(1):145-147

[38] Gaspar P, Cases O, Maroteaux L. The developmental role of serotonin: News from mouse molecular genetics. Nature Reviews. Neuroscience. 2003;**4**(12):1002-1012

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maternal depressed mood and the MTHFR C677T variant affect SLC6A4 methylation in infants at birth. PLoS One. 2010;**5**(8):2-9

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International Journal of Developmental

[56] Anderson GM, Gutknecht L, Cohen DJ, Brailly-Tabard S, Cohen JHM, Ferrari P, et al. Serotonin transporter

Functional effects and relationship to platelet hyperserotonemia. Molecular

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et al. Platelet studies in autism spectrum disorder patients and firstdegree relatives. Molecular Autism.

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Neuroscience. 2005;**23**(1):75-83

promoter variants in autism:

Psychiatry. 2002;**7**(8):831-836

Psychiatry. 2013;**74**(3):204-211

1998;**37**(7):767-776

2015;**6**(1):1-10

170-178. DOI: 10.1016/j. reprotox.2016.07.016

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[49] Li Y, Hadden C, Singh P, Mercado CP, Murphy P, Dajani NK, et al. GDMassociated insulin deficiency hinders the dissociation of SERT from ERp44 and down-regulates placental 5-HT uptake. Proceedings of the National Academy of Sciences of the United States of America. 2014;**111**(52):E5697-E5705

[50] Andalib S, Emamhadi MR, Yousefzadeh-Chabok S, Shakouri SK, Høilund-Carlsen PF, Vafaee MS, et al. Maternal SSRI exposure increases the risk of autistic offspring: A meta-analysis and systematic review. European Psychiatry. 2017;**45**:161-166. DOI: 10.1016/j.eurpsy.2017.06.001

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inhibitor use during pregnancy and newborn neurobehavior. Pediatrics.

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Vanderschuren LJMJ. Acute and constitutive increases in central serotonin levels reduce social play behaviour in peri-adolescent rats. Psychopharmacology. 2007;**195**(2):175-182

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1504-1509

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Biochemistry, and Behavior.

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neurogenesis in adolescence. PLoS One.

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2001;**34**(1):121-124

2007;**80**(1):49-56

2013;**38**(1):24-39

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[76] Kiryanova V, Dyck RH. Increased aggression, improved spatial memory, and reduced anxiety-like behaviour in adult male mice exposed to

fluoxetine early in life. Developmental Neuroscience. 2014;**36**(5):396-408

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Bulletin. 2013;**139**(5):1148-1172

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[81] Kiryanova V, Meunier SJ, Vecchiarelli HA, Hill MN, Dyck RH. Effects of maternal stress and perinatal fluoxetine exposure on behavioral outcomes of adult male offspring. Neuroscience. 2016;**320**:281-296

humans: A meta-analysis. Psychological

2014;**74**(10):1038-1051

2016;**58**(1):71-82

2015;**57**(2):141-152

2006;**26**(4):419-425

2005;**526**(1-3):218-225

**80**

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[99] Rebello TJ, Yu Q , Goodfellow NM, Caffrey Cagliostro MK, Teissier A, Morelli E, et al. Postnatal day 2 to 11 constitutes a 5-HT-sensitive period impacting adult mPFC function. The Journal of Neuroscience. 2014;**34**(37):12379-12393. DOI: 10.1523/ JNEUROSCI.1020-13.2014

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[101] Maciag D, Williams L, Coppinger D, Paul IA. Neonatal citalopram exposure produces lasting changes in behavior which are reversed by adult imipramine treatment. European Journal of Pharmacology. 2006;**532**(3):265-269

[102] Lee LJ, Lee LJH. Neonatal fluoxetine exposure alters motor performances of adolescent rats. Developmental Neurobiology. 2012;**72**(8):1122-1132

[103] Karpova NN, Lindholm J, Pruunsild P, Timmusk T, Castrén E. Long-lasting behavioural and molecular alterations induced by early postnatal fluoxetine exposure

are restored by chronic fluoxetine treatment in adult mice. European Neuropsychopharmacology. 2009;**19**(2):97-108

[104] Bairy KL, Madhyastha S, Ashok KP, Bairy I, Malini S. Developmental and behavioral consequences of prenatal fluoxetine. Pharmacology. 2007;**79**:1-11

[105] Zohar I, Shoham S, Weinstock M. Perinatal citalopram does not prevent the effect of prenatal stress on anxiety, depressive-like behaviour and serotonergic transmission in adult rat offspring. The European Journal of Neuroscience. 2015;**43**(4):590-600

[106] Hansen H, Sanchez C, Meier E. Neonatal administration of the selective serotonin reuptake inhibitor Lu 10-134-C increases forced swimminginduced immobility in adult rats: A putative animal model of depression? The Journal of Pharmacology and Experimental Therapeutics. 1997;**283**(3):1333-1341

[107] Toffoli LV, Rodrigues GM, Oliveira JF, Silva AS, Moreira EG, Pelosi GG, et al. Maternal exposure to fluoxetine during gestation and lactation affects the DNA methylation programming of rat's offspring: Modulation by folic acid supplementation. Behavioural Brain Research. 2014;**265**:142-147

[108] Knaepen L, Rayen I, Charlier TD, Fillet M, Houbart V, van Kleef M, et al. Developmental fluoxetine exposure normalizes the long-term effects of maternal stress on post-operative pain in Sprague-Dawley rat offspring. PLoS One. 2013;**8**(2):e57608

[109] Glover ME, Pugh PC, Jackson NL, Cohen JL, Fant AD, Akil H, et al. Earlylife exposure to the SSRI paroxetine exacerbates depression-like behavior in anxiety/depression-prone rats. Neuroscience. 2015;**284**:775-797

[110] Boulle F, Pawluski JL, Homberg JR, Machiels B, Kroeze Y, Kumar N, et al.

Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring. Hormones and Behavior. 2016;**80**:47-57

[111] Coleman FH, Christensen HD, Gonzalez CL, Rayburn WF. Behavioral changes in developing mice after prenatal exposure to paroxetine (Paxil). American Journal of Obstetrics and Gynecology. 1999;**181**:1166-1171

[112] McAllister BB, Kiryanova V, Dyck RH. Behavioural outcomes of perinatal maternal fluoxetine treatment. Neuroscience. 2012;**226**:356-366

[113] Krishnan V, Nestler E. Animal models of depression: Molecular perspectives Vaishnav. Current Topics in Behavioral Neurosciences. 2011;**7**:121-147

[114] Porsolt RD, Le Pichon M, Jalfre M. Depression: A new animal model sensitive to antidepressant treatments. Nature. 1977;**266**(5604):730-732

[115] Glover ME, Clinton SM. Of rodents and humans: A comparative review of the neurobehavioral effects of early life SSRI exposure in preclinical and clinical research. International Journal of Developmental Neuroscience. 2016;**51**:50-72

[116] Hilakivi L, Hilakivi I. Increased adult behavioral "despair" in rats neonatally exposed to desipramine or zimeldine: An animal model of depression? Pharmacology, Biochemistry, and Behavior. 1987;**28**(3):367-369

[117] Velazquez-Moctezuma J, Diaz RO. Neonatal treatment with clomipramine increased immobility in the forced swim test: An attribute of animal models of depression. Pharmacology, Biochemistry, and Behavior. 1992;**42**(4):737-739

**83**

*Influences of Maternal Vulnerability and Antidepressant Treatment during Pregnancy…*

in serotonin uptake during postnatal development: Evidence from sleep, stress, and behavior. The Journal of Neuroscience. 2008;**28**(14):3546-3554

[125] Francis-Oliveira J, Ponte B, Barbosa APM, Veríssimo LF, Gomes MV, Pelosi GG, et al. Fluoxetine exposure during pregnancy and lactation: Effects on acute stress response and behavior in the novelty-suppressed feeding are age and gender-dependent in rats. Behavioural Brain Research. 2013;**252**:195-203

[126] van Bodegom M, Homberg JR, Henckens MJAG. Modulation of the hypothalamic-pituitary-adrenal axis by early life stress exposure. Frontiers in Cellular Neuroscience. 2017;**11**:1-33

[127] Daniels WMU, Pietersen CY, Carstens ME, Stein DJ. Maternal separation in rats leads to anxiety-like behavior and a blunted ACTH response and altered neurotransmitter levels in response to a subsequent stressor. Metabolic Brain Disease. 2004;**19**:3-14

[128] Houwing DJ, Ramsteijn AS, Riemersma IW, Olivier JDA. Maternal separation induces anhedonia in female heterozygous serotonin transporter knockout rats. Behavioural Brain Research. 2019;**356**:204-207

[129] Lee JH, Kim HJ, Kim JG, Ryu V, Kim BT, Kang DW, et al. Depressive behaviors and decreased expression of serotonin reuptake transporter in rats that experienced neonatal maternal separation. Neuroscience Research.

[130] Wei L, David A, Duman RS, Anisman H, Kaffman A. Early life stress increases anxiety-like behavior in Balbc mice despite a compensatory increase in levels of postnatal maternal

care. Hormones and Behavior.

[131] Schmauss C, Lee-McDermott Z, Medina LR. Trans-generational effects

2007;**58**(1):32-39

2010;**57**:396-404

*DOI: http://dx.doi.org/10.5772/intechopen.83761*

[118] Bhagya V, Srikumar BN, Raju TR, Shankaranarayana Rao BS. The selective noradrenergic reuptake inhibitor reboxetine restores spatial learning deficits, biochemical changes, and hippocampal synaptic plasticity in an animal model of depression. Journal of Neuroscience Research.

[119] Yang LM, Hu B, Xia YH, Zhang BL, Zhao H. Lateral habenula lesions improve the behavioral response in depressed rats via increasing the serotonin level in dorsal raphe nucleus. Behavioural Brain Research.

[120] Vazquez-Palacios G, Bonilla-Jaime

[121] Limón-Morales O, Soria-Fregozo C, Arteaga-Silva M, Vázquez-Palacios G, Bonilla-Jaime H. Altered expression of 5-HT1A receptors in adult rats induced by neonatal treatment with clomipramine. Physiology & Behavior.

[122] Mendes-da-Silva C, De Souza SL, Barreto-Medeiros JM, De Freitas-Silva SR, Costa Antunes DE, Urbano Cunha AD, et al. Neonatal treatment with fluoxetine reduces depressive behavior induced by forced swim in adult rats. Arquivos de Neuro-Psiquiatria.

[123] Liu M-Y, Yin C-Y, Zhu L-J, Zhu X-H, Xu C, Luo C-X, et al. Sucrose preference test for measurement of stress-induced anhedonia in mice. Nature Protocols.

[124] Popa D, Lena C, Alexandre C, Adrien J. Lasting syndrome of depression produced by reduction

2015;**93**(1):104-120

2008;**188**(1):84-90

2014;**124**:37-44

2002;**60**(4):928-931

2018;**13**(7):1686-1698

H, Velazquez-Moctezuma J. Antidepressant effects of nicotine and fluoxetine in an animal model of depression induced by neonatal treatment with clomipramine. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2005;**29**:39-46

*Influences of Maternal Vulnerability and Antidepressant Treatment during Pregnancy… DOI: http://dx.doi.org/10.5772/intechopen.83761*

[118] Bhagya V, Srikumar BN, Raju TR, Shankaranarayana Rao BS. The selective noradrenergic reuptake inhibitor reboxetine restores spatial learning deficits, biochemical changes, and hippocampal synaptic plasticity in an animal model of depression. Journal of Neuroscience Research. 2015;**93**(1):104-120

*Antidepressants - Preclinical, Clinical and Translational Aspects*

Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring. Hormones and Behavior.

[111] Coleman FH, Christensen HD, Gonzalez CL, Rayburn WF. Behavioral changes in developing mice after prenatal exposure to paroxetine (Paxil). American Journal of Obstetrics and Gynecology. 1999;**181**:1166-1171

[112] McAllister BB, Kiryanova V, Dyck RH. Behavioural outcomes of perinatal maternal fluoxetine treatment.

Neuroscience. 2012;**226**:356-366

[113] Krishnan V, Nestler E. Animal models of depression: Molecular perspectives Vaishnav. Current Topics in Behavioral Neurosciences.

[114] Porsolt RD, Le Pichon M, Jalfre M. Depression: A new animal model sensitive to antidepressant treatments. Nature. 1977;**266**(5604):730-732

[115] Glover ME, Clinton SM. Of rodents and humans: A comparative review of the neurobehavioral effects of early life SSRI exposure in preclinical and clinical research. International Journal of Developmental Neuroscience.

[116] Hilakivi L, Hilakivi I. Increased adult behavioral "despair" in rats neonatally exposed to desipramine or zimeldine: An animal model of depression? Pharmacology, Biochemistry, and Behavior.

2016;**80**:47-57

2011;**7**:121-147

2016;**51**:50-72

1987;**28**(3):367-369

[117] Velazquez-Moctezuma J, Diaz RO. Neonatal treatment with clomipramine increased immobility in the forced swim test: An attribute of animal models of depression. Pharmacology, Biochemistry, and Behavior. 1992;**42**(4):737-739

are restored by chronic fluoxetine treatment in adult mice. European Neuropsychopharmacology.

[104] Bairy KL, Madhyastha S, Ashok KP, Bairy I, Malini S. Developmental and behavioral consequences of prenatal fluoxetine. Pharmacology. 2007;**79**:1-11

[105] Zohar I, Shoham S, Weinstock M. Perinatal citalopram does not prevent the effect of prenatal stress on

anxiety, depressive-like behaviour and serotonergic transmission in adult rat offspring. The European Journal of Neuroscience. 2015;**43**(4):590-600

[106] Hansen H, Sanchez C, Meier E. Neonatal administration of the selective

[107] Toffoli LV, Rodrigues GM, Oliveira JF, Silva AS, Moreira EG, Pelosi GG, et al. Maternal exposure to fluoxetine during gestation and lactation affects the DNA methylation programming of rat's offspring: Modulation by folic acid supplementation. Behavioural Brain

[108] Knaepen L, Rayen I, Charlier TD, Fillet M, Houbart V, van Kleef M, et al. Developmental fluoxetine exposure normalizes the long-term effects of maternal stress on post-operative pain in Sprague-Dawley rat offspring. PLoS

[109] Glover ME, Pugh PC, Jackson NL, Cohen JL, Fant AD, Akil H, et al. Earlylife exposure to the SSRI paroxetine exacerbates depression-like behavior in anxiety/depression-prone rats. Neuroscience. 2015;**284**:775-797

[110] Boulle F, Pawluski JL, Homberg JR, Machiels B, Kroeze Y, Kumar N, et al.

serotonin reuptake inhibitor Lu 10-134-C increases forced swimminginduced immobility in adult rats: A putative animal model of depression?

The Journal of Pharmacology and Experimental Therapeutics.

Research. 2014;**265**:142-147

One. 2013;**8**(2):e57608

1997;**283**(3):1333-1341

2009;**19**(2):97-108

**82**

[119] Yang LM, Hu B, Xia YH, Zhang BL, Zhao H. Lateral habenula lesions improve the behavioral response in depressed rats via increasing the serotonin level in dorsal raphe nucleus. Behavioural Brain Research. 2008;**188**(1):84-90

[120] Vazquez-Palacios G, Bonilla-Jaime H, Velazquez-Moctezuma J. Antidepressant effects of nicotine and fluoxetine in an animal model of depression induced by neonatal treatment with clomipramine. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2005;**29**:39-46

[121] Limón-Morales O, Soria-Fregozo C, Arteaga-Silva M, Vázquez-Palacios G, Bonilla-Jaime H. Altered expression of 5-HT1A receptors in adult rats induced by neonatal treatment with clomipramine. Physiology & Behavior. 2014;**124**:37-44

[122] Mendes-da-Silva C, De Souza SL, Barreto-Medeiros JM, De Freitas-Silva SR, Costa Antunes DE, Urbano Cunha AD, et al. Neonatal treatment with fluoxetine reduces depressive behavior induced by forced swim in adult rats. Arquivos de Neuro-Psiquiatria. 2002;**60**(4):928-931

[123] Liu M-Y, Yin C-Y, Zhu L-J, Zhu X-H, Xu C, Luo C-X, et al. Sucrose preference test for measurement of stress-induced anhedonia in mice. Nature Protocols. 2018;**13**(7):1686-1698

[124] Popa D, Lena C, Alexandre C, Adrien J. Lasting syndrome of depression produced by reduction

in serotonin uptake during postnatal development: Evidence from sleep, stress, and behavior. The Journal of Neuroscience. 2008;**28**(14):3546-3554

[125] Francis-Oliveira J, Ponte B, Barbosa APM, Veríssimo LF, Gomes MV, Pelosi GG, et al. Fluoxetine exposure during pregnancy and lactation: Effects on acute stress response and behavior in the novelty-suppressed feeding are age and gender-dependent in rats. Behavioural Brain Research. 2013;**252**:195-203

[126] van Bodegom M, Homberg JR, Henckens MJAG. Modulation of the hypothalamic-pituitary-adrenal axis by early life stress exposure. Frontiers in Cellular Neuroscience. 2017;**11**:1-33

[127] Daniels WMU, Pietersen CY, Carstens ME, Stein DJ. Maternal separation in rats leads to anxiety-like behavior and a blunted ACTH response and altered neurotransmitter levels in response to a subsequent stressor. Metabolic Brain Disease. 2004;**19**:3-14

[128] Houwing DJ, Ramsteijn AS, Riemersma IW, Olivier JDA. Maternal separation induces anhedonia in female heterozygous serotonin transporter knockout rats. Behavioural Brain Research. 2019;**356**:204-207

[129] Lee JH, Kim HJ, Kim JG, Ryu V, Kim BT, Kang DW, et al. Depressive behaviors and decreased expression of serotonin reuptake transporter in rats that experienced neonatal maternal separation. Neuroscience Research. 2007;**58**(1):32-39

[130] Wei L, David A, Duman RS, Anisman H, Kaffman A. Early life stress increases anxiety-like behavior in Balbc mice despite a compensatory increase in levels of postnatal maternal care. Hormones and Behavior. 2010;**57**:396-404

[131] Schmauss C, Lee-McDermott Z, Medina LR. Trans-generational effects of early life stress: The role of maternal behavior. Scientific Reports. 2014;**4**:1-11

[132] Gemmel M, Kokras N, Dalla C, Pawluski JL. Perinatal fluoxetine prevents the effect of pre-gestational maternal stress on 5-HT in the PFC, but maternal stress has enduring effects on mPFC synaptic structure in offspring. Neuropharmacology. 2018;**128**:168-180

[133] Rayen I, Steinbusch HWM, Charlier TD, Pawluski JL. Developmental fluoxetine exposure and prenatal stress alter sexual differentiation of the brain and reproductive behavior in male rat offspring. Psychoneuroendocrinology. 2013;**38**(9):1618-1629

[134] Boulle F, Pawluski JL, Homberg JR, Machiels B, Kroeze Y, Kumar N, et al. Prenatal stress and early-life exposure to fluoxetine have enduring effects on anxiety and hippocampal BDNF gene expression in adult male offspring. Developmental Psychobiology. 2016;**58**(4):427-438

[135] Salari AA, Fatehi-Gharehlar L, Motayagheni N, Homberg JR. Fluoxetine normalizes the effects of prenatal maternal stress on depressionand anxiety-like behaviors in mouse dams and male offspring. Behavioural Brain Research. 2016;**311**:354-367

**85**

thalamocortical axons

antidepressants drugs.

**1. Introduction**

**Chapter 5**

**Abstract**

Orexin 2 Receptor Antagonists

to Rodent Behavioral Screens

tion for orexin receptor antagonists beyond simply improving sleep.

**Keywords:** antidepressant drug screens, excitatory postsynaptic potential currents (EPSCs), DOI-induced head twitches, differential-reinforcement-of-low-rate 72-s (DRL 72-s) behavior, LSN2424100, layer V pyramidal neurons, prefrontal cortex,

Only approximately 50–60% of patients experience an antidepressant response when treated with selective reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) [1–3]. Even those patients that do respond often continue to experience residual symptoms such as insomnia and cognitive dysfunction [4–7]. Thus, novel antidepressant medications are needed that treat a broader expanse of symptoms or are effective in patients that have failed several different classes of

The primary well-documented augmentation treatment for depressed patients already on SSRIs or SNRIs are atypical antipsychotics (aripiprazole, quetiapine,

*Gerard J. Marek, Stephen Chaney and Mark J. Benvenga*

from Prefrontal Cortical Circuitry

Orexin is a neuropeptide contained in neurons from several hypothalamic nuclei that project throughout the forebrain analogously to monoamines synthesized by brainstem nuclei. Orexin, like 5-hydroxytryptamine (5-HT), norepinephrine (NE), dopamine (DA), histamine and acetylcholine (ACh) exerts prominent effects on the sleep-wake cycle of all mammals. Activation of the orexin2 receptor appears to induce spontaneous excitatory synaptic currents (EPSCs) on layer V pyramidal neurons due to release of glutamate from thalamocortical terminals similar to activation of 5-HT2A and α1-adrenergic receptors. Layer V pyramidal cells are the major descending output cell in the prefrontal cortex with projections to the thalamus, striatum, amygdala, brainstem and spinal cord. In keeping with salient modulation of prefrontal cortical physiology, orexin2 receptor antagonists exert similar effects to 5-HT2A receptor antagonists in suppressing hallucinogen (e.g., DOI)-induced head twitches and producing antidepressant-like effects on the differentialreinforcement-of-low-rate 72-s (DRL 72-s) schedule of reinforcement. Currently, there is both negative and some preliminary positive evidence that blocking orexin2 receptors may result in antidepressant efficacy in patients with major depressive disorder. Overall, the treatment of mood disorders is an additional potential indica-

#### **Chapter 5**

*Antidepressants - Preclinical, Clinical and Translational Aspects*

of early life stress: The role of maternal behavior. Scientific Reports. 2014;**4**:1-11

[132] Gemmel M, Kokras N, Dalla C, Pawluski JL. Perinatal fluoxetine prevents the effect of pre-gestational maternal stress on 5-HT in the PFC, but maternal stress has enduring effects on mPFC synaptic structure in offspring. Neuropharmacology. 2018;**128**:168-180

[133] Rayen I, Steinbusch HWM, Charlier TD, Pawluski JL.

2013;**38**(9):1618-1629

2016;**58**(4):427-438

Developmental fluoxetine exposure and prenatal stress alter sexual differentiation of the brain and reproductive behavior in male rat offspring. Psychoneuroendocrinology.

[134] Boulle F, Pawluski JL, Homberg JR, Machiels B, Kroeze Y, Kumar N, et al. Prenatal stress and early-life exposure to fluoxetine have enduring effects on anxiety and hippocampal BDNF gene expression in adult male offspring. Developmental Psychobiology.

[135] Salari AA, Fatehi-Gharehlar L, Motayagheni N, Homberg JR. Fluoxetine normalizes the effects of prenatal maternal stress on depressionand anxiety-like behaviors in mouse dams and male offspring. Behavioural Brain Research. 2016;**311**:354-367

**84**

## Orexin 2 Receptor Antagonists from Prefrontal Cortical Circuitry to Rodent Behavioral Screens

*Gerard J. Marek, Stephen Chaney and Mark J. Benvenga*

#### **Abstract**

Orexin is a neuropeptide contained in neurons from several hypothalamic nuclei that project throughout the forebrain analogously to monoamines synthesized by brainstem nuclei. Orexin, like 5-hydroxytryptamine (5-HT), norepinephrine (NE), dopamine (DA), histamine and acetylcholine (ACh) exerts prominent effects on the sleep-wake cycle of all mammals. Activation of the orexin2 receptor appears to induce spontaneous excitatory synaptic currents (EPSCs) on layer V pyramidal neurons due to release of glutamate from thalamocortical terminals similar to activation of 5-HT2A and α1-adrenergic receptors. Layer V pyramidal cells are the major descending output cell in the prefrontal cortex with projections to the thalamus, striatum, amygdala, brainstem and spinal cord. In keeping with salient modulation of prefrontal cortical physiology, orexin2 receptor antagonists exert similar effects to 5-HT2A receptor antagonists in suppressing hallucinogen (e.g., DOI)-induced head twitches and producing antidepressant-like effects on the differentialreinforcement-of-low-rate 72-s (DRL 72-s) schedule of reinforcement. Currently, there is both negative and some preliminary positive evidence that blocking orexin2 receptors may result in antidepressant efficacy in patients with major depressive disorder. Overall, the treatment of mood disorders is an additional potential indication for orexin receptor antagonists beyond simply improving sleep.

**Keywords:** antidepressant drug screens, excitatory postsynaptic potential currents (EPSCs), DOI-induced head twitches, differential-reinforcement-of-low-rate 72-s (DRL 72-s) behavior, LSN2424100, layer V pyramidal neurons, prefrontal cortex, thalamocortical axons

#### **1. Introduction**

Only approximately 50–60% of patients experience an antidepressant response when treated with selective reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) [1–3]. Even those patients that do respond often continue to experience residual symptoms such as insomnia and cognitive dysfunction [4–7]. Thus, novel antidepressant medications are needed that treat a broader expanse of symptoms or are effective in patients that have failed several different classes of antidepressants drugs.

The primary well-documented augmentation treatment for depressed patients already on SSRIs or SNRIs are atypical antipsychotics (aripiprazole, quetiapine,

risperidone or olanzapine) and less so for mirtazapine/mianserin [8–12]. The common pharmacological action shared by these medications is blockade of 5-HT2A receptors [13]. Blockade of 5-HT2A receptors may also be a key pharmacological feature for most tricyclic antidepressant drugs which explain their greater antidepressant efficacy compared to SSRIs [14–17]. However, side effects especially problematic for augmentation of SSRIs/SNRIs with atypical antipsychotic drugs are weight gain and extrapyramidal symptoms. Thus, discovery of a drug targeted on key neurocircuitry modulated by 5-HT2A receptors is one strategy to develop a novel antidepressant medication.

Given that pathophysiology of mood disorders appears to involve the prefrontal cortex and associated macrocircuits, an obvious candidate brain region to provide a context for 5-HT2A receptor blockade at augmenting the effects of SSRIs/ SNRIs is the prefrontal cortex [18–21]. In particular, layer V pyramidal neurons can effectively modulate important cortical circuits (including corticothalamic, corticostriatal, cortico-amydalar and cortico-brainstem) that impact mood, cognition/executive function, sleep and appetite [22, 23]. One aspect of 5-HT2A receptor function largely restricted to layer V pyramidal cells is increasing the frequency of spontaneous excitatory postsynaptic currents/potentials (EPSC/EPSPs) onto the dendritic branches [24]. This effect appears to be mediated by AMPA receptor stimulation of directly on the layer V pyramidal cells [24, 25]. Lesion studies have suggested that 5-HT2A receptor activation is releasing glutamate from thalamocortical terminals arising from the "non-specific" midline and intralaminar thalamic nuclei [26, 27]. There appear to be hot spots in layer I and layer Va where focal 5-HT-induced release of glutamate sensitive to the sodium channel blocker tetrodotoxin (TTX) occurs, although an amplification of postsynaptic currents, including TTX-sensitive sodium currents [24]. A number of Gi/Go-coupled GPCRs (including mGlu2, mGlu4, μ-opioid, adenosine A1 receptors) also suppresses 5-HT- or DOIinduced glutamate release from these terminals [28–33]. Several other Gq/G11 coupled GPCRs (α1-adrenergic receptors and mGlu5 receptors) also appear to induce glutamate release onto layer V pyramidal neurons that are suppressed by the sodium channel blocker TTX, μ-opioid agonists, and AMPA receptor antagonists [34, 35]. This rich pharmacological modulation of 5-HT2A receptor-mediated electrophysiological effects on dendritic integration for the principle output neurons in the prefrontal cortex provides heuristic promise for drug discovery efforts with respect to major psychiatric disease, including mood disorders and schizophrenia [36, 37].

The increase in spontaneous EPSC/EPSPs upon layer V pyramidal cells induced by 5-HT2A receptor activation may be associated with other electrophysiological, biochemical and behavioral effects involving the medial prefrontal cortex (mPFC). On an electrophysiological level, electrical stimulation of the white matter below the cortex appears to result in an induction of "late" EPSC/EPSPs during washout after application of 5-HT or when the phenethylamine hallucinogen DOI is bathapplied to the cortical slice [38]. These late EPSCs are also suppressed by a range of neurotransmitter receptors that suppress spontaneous 5-HT-induced EPSCs such as agonists for mGlu2, μ-opioid, and adenosine A1 receptors [30, 32]. There are also some differences between these two electrophysiological responses as NMDA receptor stimulation appears important for the electrical stimulation/DOI-evoked responses unlike the spontaneous 5-HT-induced EPSC/EPSPs [39].

Secondly, systemic DOI administration also induces a range of immediate-early gene-like signals in the prefrontal cortex/neocortex that are also suppressed by activation of mGlu2 autoreceptors and appear dependent on glutamate release from thalamocortical terminals [40–45]. This effect of prefrontal cortical 5-HT2A receptor activation is relatively sparsely studied compared to the electrophysiological or behavioral sequelae.

**87**

*Orexin 2 Receptor Antagonists from Prefrontal Cortical Circuitry to Rodent Behavioral Screens*

on DOI-induced head twitches have been discussed elsewhere [36].

performing under the DRL 72-s schedule [51, 71–77].

Finally, an argument was advanced recently that the basis for detecting antidepressant-like drug effects on the operant differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule may be related to the biology of a range of neurotransmitter systems that interact with the 5-HT2A receptor in the prefrontal cortex to modulate motor impulsivity [69, 70]. As expected from the similar effects of 5-HT2A receptor antagonists compared to mGlu2 receptor positive allosteric modulators (PAMs) and also to adenosine A1 receptor agonists for the prefrontal electrophysiology discussed above, 5-HT2A receptor antagonists, mGlu2 receptor PAMs and adenosine A1 receptor agonists all test similar to known antidepressant drugs in rats

The underlying thesis of this chapter is that understanding how other neurotransmitter systems interact with 5-HT2A receptors in the medial prefrontal cortex on an electrophysiological, biochemical and behavioral scale may help discover novel antidepressant drugs. Orexin (OX) receptor agonists/antagonists appear to be one such neurotransmitter system that interacts with critical biological aspects of 5-HT2A receptor activation/blockade in thalamocortical pathways influencing the principle output (layer V pyramidal cells) of the prefrontal cortex in a manner suggesting that OX2 receptor antagonists are putative antidepressant medications.

**2. Orexin-2 receptor blockade and putative antidepressant action**

The orexins are two peptide neurotransmitters produced in several nuclei within the lateral hypothalamus which are intimately involved in arousal and reward [78]. The name "orexin" was originally coined from the Greek word "orexis" when the orexin/ hypocretin peptides were studied for effects on appetite. However, the more salient biological aspect of the orexin system later was realized to be altering sleep and arousal. More specifically, mutations of genes for the orexin-2 (OX2) receptor, orexin peptides, and loss of orexin-containing hypothalamic cell bodies were demonstrated to be the genetic cause of narcolepsy in canines, mice and humans. The first approved medication targeting the orexin system, suvorexant, blocks both orexin-1 (OX1) and OX2 receptors as a dual orexin receptor antagonist (DORA) and is indicated for the treatment of insomnia [78, 79]. Several other DORAs have been shown to be efficacious in treating primary insomnia [80–82]. The overlapping and diverging distribution for the OX1 and OX2 mRNA and protein has inspired several decades of past/ongoing research exploring these receptors for sleep, arousal, feeding,

Third, either systemic administration or local prefrontal cortical administration of agonists for 5-HT2A receptors induces a robust increase in the frequency of head twitches (a behavior infrequently observed under baseline condition) [46, 47]. Agonists or positive allosteric modulators of mGlu2, mGlu4, μ-opioid, adenosine A1 receptors also suppress DOI-induced head twitches [28, 31, 48–52]. Naturally, these head twitches induced by direct 5-HT2A receptor agonists are also suppressed by a number of antidepressant drugs that potently block 5-HT2A receptors or downregulate 5-HT2A receptors such as mirtazapine [53], mianserin [54–57], trazodone [55, 58–60], nefazodone [58, 61] and tricyclic antidepressants [55, 57, 62–68] Some of the tricyclic antidepressants are active only with chronic daily administration. While the antidepressant and monoamine oxidase inhibitor (MAOI) tranylcypromine does not directly bind to 5-HT2A receptors, chronic daily administration of this antidepressant has been found to suppress 5-methoxy-N,N-dimethyltryptamine-induced head twitches under conditions associated with a down-regulation of 5-HT2A receptors [63]. The clinical lore regarding μ-opioid receptor agonists and potential antidepressant action is intriguing in light of effects for this class of drugs

*DOI: http://dx.doi.org/10.5772/intechopen.82544*

#### *Orexin 2 Receptor Antagonists from Prefrontal Cortical Circuitry to Rodent Behavioral Screens DOI: http://dx.doi.org/10.5772/intechopen.82544*

Third, either systemic administration or local prefrontal cortical administration of agonists for 5-HT2A receptors induces a robust increase in the frequency of head twitches (a behavior infrequently observed under baseline condition) [46, 47]. Agonists or positive allosteric modulators of mGlu2, mGlu4, μ-opioid, adenosine A1 receptors also suppress DOI-induced head twitches [28, 31, 48–52]. Naturally, these head twitches induced by direct 5-HT2A receptor agonists are also suppressed by a number of antidepressant drugs that potently block 5-HT2A receptors or downregulate 5-HT2A receptors such as mirtazapine [53], mianserin [54–57], trazodone [55, 58–60], nefazodone [58, 61] and tricyclic antidepressants [55, 57, 62–68] Some of the tricyclic antidepressants are active only with chronic daily administration. While the antidepressant and monoamine oxidase inhibitor (MAOI) tranylcypromine does not directly bind to 5-HT2A receptors, chronic daily administration of this antidepressant has been found to suppress 5-methoxy-N,N-dimethyltryptamine-induced head twitches under conditions associated with a down-regulation of 5-HT2A receptors [63]. The clinical lore regarding μ-opioid receptor agonists and potential antidepressant action is intriguing in light of effects for this class of drugs on DOI-induced head twitches have been discussed elsewhere [36].

Finally, an argument was advanced recently that the basis for detecting antidepressant-like drug effects on the operant differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule may be related to the biology of a range of neurotransmitter systems that interact with the 5-HT2A receptor in the prefrontal cortex to modulate motor impulsivity [69, 70]. As expected from the similar effects of 5-HT2A receptor antagonists compared to mGlu2 receptor positive allosteric modulators (PAMs) and also to adenosine A1 receptor agonists for the prefrontal electrophysiology discussed above, 5-HT2A receptor antagonists, mGlu2 receptor PAMs and adenosine A1 receptor agonists all test similar to known antidepressant drugs in rats performing under the DRL 72-s schedule [51, 71–77].

The underlying thesis of this chapter is that understanding how other neurotransmitter systems interact with 5-HT2A receptors in the medial prefrontal cortex on an electrophysiological, biochemical and behavioral scale may help discover novel antidepressant drugs. Orexin (OX) receptor agonists/antagonists appear to be one such neurotransmitter system that interacts with critical biological aspects of 5-HT2A receptor activation/blockade in thalamocortical pathways influencing the principle output (layer V pyramidal cells) of the prefrontal cortex in a manner suggesting that OX2 receptor antagonists are putative antidepressant medications.

#### **2. Orexin-2 receptor blockade and putative antidepressant action**

The orexins are two peptide neurotransmitters produced in several nuclei within the lateral hypothalamus which are intimately involved in arousal and reward [78]. The name "orexin" was originally coined from the Greek word "orexis" when the orexin/ hypocretin peptides were studied for effects on appetite. However, the more salient biological aspect of the orexin system later was realized to be altering sleep and arousal. More specifically, mutations of genes for the orexin-2 (OX2) receptor, orexin peptides, and loss of orexin-containing hypothalamic cell bodies were demonstrated to be the genetic cause of narcolepsy in canines, mice and humans. The first approved medication targeting the orexin system, suvorexant, blocks both orexin-1 (OX1) and OX2 receptors as a dual orexin receptor antagonist (DORA) and is indicated for the treatment of insomnia [78, 79]. Several other DORAs have been shown to be efficacious in treating primary insomnia [80–82]. The overlapping and diverging distribution for the OX1 and OX2 mRNA and protein has inspired several decades of past/ongoing research exploring these receptors for sleep, arousal, feeding,

*Antidepressants - Preclinical, Clinical and Translational Aspects*

antidepressant medication.

risperidone or olanzapine) and less so for mirtazapine/mianserin [8–12]. The common pharmacological action shared by these medications is blockade of 5-HT2A receptors [13]. Blockade of 5-HT2A receptors may also be a key pharmacological feature for most tricyclic antidepressant drugs which explain their greater antidepressant efficacy compared to SSRIs [14–17]. However, side effects especially problematic for augmentation of SSRIs/SNRIs with atypical antipsychotic drugs are weight gain and extrapyramidal symptoms. Thus, discovery of a drug targeted on key neurocircuitry modulated by 5-HT2A receptors is one strategy to develop a novel

Given that pathophysiology of mood disorders appears to involve the prefrontal

cortex and associated macrocircuits, an obvious candidate brain region to provide a context for 5-HT2A receptor blockade at augmenting the effects of SSRIs/ SNRIs is the prefrontal cortex [18–21]. In particular, layer V pyramidal neurons can effectively modulate important cortical circuits (including corticothalamic, corticostriatal, cortico-amydalar and cortico-brainstem) that impact mood, cognition/executive function, sleep and appetite [22, 23]. One aspect of 5-HT2A receptor function largely restricted to layer V pyramidal cells is increasing the frequency of spontaneous excitatory postsynaptic currents/potentials (EPSC/EPSPs) onto the dendritic branches [24]. This effect appears to be mediated by AMPA receptor stimulation of directly on the layer V pyramidal cells [24, 25]. Lesion studies have suggested that 5-HT2A receptor activation is releasing glutamate from thalamocortical terminals arising from the "non-specific" midline and intralaminar thalamic nuclei [26, 27]. There appear to be hot spots in layer I and layer Va where focal 5-HT-induced release of glutamate sensitive to the sodium channel blocker tetrodotoxin (TTX) occurs, although an amplification of postsynaptic currents, including TTX-sensitive sodium currents [24]. A number of Gi/Go-coupled GPCRs (including mGlu2, mGlu4, μ-opioid, adenosine A1 receptors) also suppresses 5-HT- or DOIinduced glutamate release from these terminals [28–33]. Several other Gq/G11 coupled GPCRs (α1-adrenergic receptors and mGlu5 receptors) also appear to induce glutamate release onto layer V pyramidal neurons that are suppressed by the sodium channel blocker TTX, μ-opioid agonists, and AMPA receptor antagonists [34, 35]. This rich pharmacological modulation of 5-HT2A receptor-mediated electrophysiological effects on dendritic integration for the principle output neurons in the prefrontal cortex provides heuristic promise for drug discovery efforts with respect to major psychiatric disease, including mood disorders and schizophrenia [36, 37]. The increase in spontaneous EPSC/EPSPs upon layer V pyramidal cells induced by 5-HT2A receptor activation may be associated with other electrophysiological, biochemical and behavioral effects involving the medial prefrontal cortex (mPFC). On an electrophysiological level, electrical stimulation of the white matter below the cortex appears to result in an induction of "late" EPSC/EPSPs during washout after application of 5-HT or when the phenethylamine hallucinogen DOI is bathapplied to the cortical slice [38]. These late EPSCs are also suppressed by a range of neurotransmitter receptors that suppress spontaneous 5-HT-induced EPSCs such as agonists for mGlu2, μ-opioid, and adenosine A1 receptors [30, 32]. There are also some differences between these two electrophysiological responses as NMDA receptor stimulation appears important for the electrical stimulation/DOI-evoked

responses unlike the spontaneous 5-HT-induced EPSC/EPSPs [39].

Secondly, systemic DOI administration also induces a range of immediate-early gene-like signals in the prefrontal cortex/neocortex that are also suppressed by activation of mGlu2 autoreceptors and appear dependent on glutamate release from thalamocortical terminals [40–45]. This effect of prefrontal cortical 5-HT2A receptor activation is relatively sparsely studied compared to the electrophysiological or

**86**

behavioral sequelae.

alcohol and drug self-administration, stress, anxiety and depression models [83]. The involvement of OX2 receptors in arousal together with the presence of OX2 receptor mRNA in the non-specific midline and intralaminar thalamic nuclei and the interactions of the orexin system with brainstem nuclei with overlapping monoamine projections makes the OX2 receptor an especially interesting target for mood disorder therapeutics [78, 83]. As discussed below, OX2 or hypocretin-2 receptor blockade appears to be a mechanism of action that provides a means of testing the hypothesis discussed above where a drug appropriately modifying multiple levels of biological effects for 5-HT2A receptor activation in the mPFC would be a putative antidepressant medication.

Electrophysiological effects of OX2 receptor activation in the prefrontal cortex appear to parallel certain effects of 5-HT2A receptor activation when recording from layer V pyramidal neurons. The orexin-B (hypocretin-2) peptide was found to increase spontaneous EPSC/EPSPs in layer V pyramidal neurons of the prefrontal cortex that were blocked by postsynaptic AMPA receptor antagonists as well as by TTX and u-opioid agonists on the presynaptic side similar to the case for 5-HT2A receptor stimulation [84]. Experiments to delineate the origin of afferents in the PFC from which orexin induced glutamate release from suggested that the cells of origin were in the midline and intralaminar thalamic nuclei [84]. Further, the relative potency for orexin-B compared to orexin-A (hypocretin-1) at inducing spontaneous OX-induced EPSCs/EPSPs in PFC layer V pyramidal cells is similar to that found in the intralaminar and midline thalamic nuclei with OX2, not OX1, receptor responses [84–86]. The tetrodotoxin sensitivity of the orexin-induced EPSCs/ EPSPs is in keeping with earlier studies suggesting that thalamocortical projections from these "non-specific" thalamic nuclei associated with arousal were prone to the generation of terminal spikes as previously suggested [87, 88]. This dependence on thalamocortical pathways originating in the midline and intralaminar thalamic nuclei and terminating in layers I and Va of the prefrontal cortex is consistent with features for the spontaneous 5-HT-induced EPSCs/EPSPs [26, 27]. One difference between OX-induced spontaneous EPSCs and 5-HT-induced EPSCS is that OX does not appear to induce postsynaptic depolarization (consistent with absence of OX2 mRNA in layer V pyramidal cells) unlike the case for 5-HT2A receptor activation in the majority of layer V pyramidal cells [84, 89]. However, studies characterizing the ability of orexin-B induced EPSCs/EPSPs to be blocked with selective OX2 receptor antagonists or selective OX1 receptor antagonists would be useful to unambiguously identify the OX receptor subtype involved in this response.

Limited work has been done exploring effects of OX2 receptor antagonists on immediate early gene (IEG-like) responses in the prefrontal cortex. However, the OX2 receptor antagonist LSN2424100 did suppress restraint stress-induced increases in c-Fos protein expression without having any effects on baseline Fos protein expression in the home cage [90]. These effects of the OX2 receptor antagonist LSN2424100 on restraint stress-induced increases Fos expression in the prelimbic cortex are similar to an effect of the mGlu2 receptor agonist LY354740 on restraint stress-induced increases in Fos expression [45]. As discussed above, 5-HT2A receptor agonists induce a number of immediate IEG-like responses in the prefrontal cortex. Activation of mGlu2 receptors appears to suppress the DOI-induced increases in a number of IEG-like responses in the prefrontal cortex [40, 41, 44, 91].

Modulation of 5-HT2A receptor agonist-induced head twitches is a behavioral measure that is suppressed by a range of antidepressants blocking/regulating 5-HT2A receptors as discussed above; these DOI-induced head twitches are also suppressed by the selective OX2 receptor antagonist LSN2424100 (**Figure 1**). LSN2424100 possesses approximately 200-fold functional OX2 receptor antagonist activity at both human recombinant OX2 vs. OX1 receptors or rat OX2 vs. OX1

**89**

**Figure 1.**

*Orexin 2 Receptor Antagonists from Prefrontal Cortical Circuitry to Rodent Behavioral Screens*

receptors [90]. Administration of LSN2424100 (10 mg/kg, i.p.) 30 min prior to administration of DOI (3 mg/kg, i.p.) with behavioral observations beginning 5 min later for a 30 min period resulted in over a 67% statistically significant reduction in the frequency of DOI-induced head twitches in CD-1 mice (n = 8/group; **Figure 1**) using conditions/methods/statistical analyses reported elsewhere in greater detail [52]. Head twitches were observed in 8/8 vehicle/DOI treated mice but in only 3/8 LSN2424100/DOI treated mice (p < 0.05, Fisher's Exact Test). This experiment demonstrating that a Gq/G11-coupled GCPR OX2 receptor antagonist (like 5-HT2A receptor antagonists) suppress DOI-induced head twitches fits in with evidence that agonists or positive allosteric modulators of Gi/Go-coupled GCPRs (mGlu2, mGlu4, adenosine A1, and μ-opioid receptors) similarly suppress DOIinduce head twitches [28, 31, 48, 50, 52, 92, 93]. Thus, the effects of these drugs on spontaneous EPSCs/EPSPs upon layer V pyramidal neuron apical dendrites in layers I and Va of the prefrontal cortex all produce directionally consistent effects on DOIinduced head twitches [37]. These results imply that adequate orexin, glutamate, adenosine and endogenous opioid release is present from or onto thalamocortical afferents under the in vivo experimental conditions employed to engender salient changes in dendritic integration of the principle output layer V pyramidal cells.

OX2 receptor antagonists also appear to modulate at least certain aspects of executive function mediated by the prefrontal cortex, namely impulsivity and biasing operant responding for DRL schedules in rodents [69, 90]. The OX2 receptor antagonist LSN2424100 increased reinforcers obtained and decreased total responses by Sprague-Dawley rats performing under a DRL 72-s schedule of reinforcement (**Figure 2**) [90]. These antidepressant-like responses were largely replicated in wild-type CD-1 mice and OX1 receptor knockout mice responding on a DRL 36-s schedule of reinforcement rate [90]. However, no changes in the reinforcement rate or response rate

*The effect of (±)-DOI (3 mg/kg, i.p.) and the selective OX2 receptor antagonist LSN2424100 (10 mg/kg, i.p.) on head twitches in CD-1 wild-type mice observed for 30 min following drug administration. LSN2424100 was administered 30 min prior to DOI. Each bar represents the mean (± SEM) of eight mice. Significantly different from the mean number of head twitches for the vehicle/DOI group, \* p < 0.05. Significantly different from the number of mice displaying head twitches for the vehicle/DOI group, # p < 0.05 by the Fisher exact test.*

*DOI: http://dx.doi.org/10.5772/intechopen.82544*

#### *Orexin 2 Receptor Antagonists from Prefrontal Cortical Circuitry to Rodent Behavioral Screens DOI: http://dx.doi.org/10.5772/intechopen.82544*

receptors [90]. Administration of LSN2424100 (10 mg/kg, i.p.) 30 min prior to administration of DOI (3 mg/kg, i.p.) with behavioral observations beginning 5 min later for a 30 min period resulted in over a 67% statistically significant reduction in the frequency of DOI-induced head twitches in CD-1 mice (n = 8/group; **Figure 1**) using conditions/methods/statistical analyses reported elsewhere in greater detail [52]. Head twitches were observed in 8/8 vehicle/DOI treated mice but in only 3/8 LSN2424100/DOI treated mice (p < 0.05, Fisher's Exact Test). This experiment demonstrating that a Gq/G11-coupled GCPR OX2 receptor antagonist (like 5-HT2A receptor antagonists) suppress DOI-induced head twitches fits in with evidence that agonists or positive allosteric modulators of Gi/Go-coupled GCPRs (mGlu2, mGlu4, adenosine A1, and μ-opioid receptors) similarly suppress DOIinduce head twitches [28, 31, 48, 50, 52, 92, 93]. Thus, the effects of these drugs on spontaneous EPSCs/EPSPs upon layer V pyramidal neuron apical dendrites in layers I and Va of the prefrontal cortex all produce directionally consistent effects on DOIinduced head twitches [37]. These results imply that adequate orexin, glutamate, adenosine and endogenous opioid release is present from or onto thalamocortical afferents under the in vivo experimental conditions employed to engender salient changes in dendritic integration of the principle output layer V pyramidal cells.

OX2 receptor antagonists also appear to modulate at least certain aspects of executive function mediated by the prefrontal cortex, namely impulsivity and biasing operant responding for DRL schedules in rodents [69, 90]. The OX2 receptor antagonist LSN2424100 increased reinforcers obtained and decreased total responses by Sprague-Dawley rats performing under a DRL 72-s schedule of reinforcement (**Figure 2**) [90]. These antidepressant-like responses were largely replicated in wild-type CD-1 mice and OX1 receptor knockout mice responding on a DRL 36-s schedule of reinforcement rate [90]. However, no changes in the reinforcement rate or response rate

#### **Figure 1.**

*Antidepressants - Preclinical, Clinical and Translational Aspects*

identify the OX receptor subtype involved in this response.

number of IEG-like responses in the prefrontal cortex [40, 41, 44, 91].

Limited work has been done exploring effects of OX2 receptor antagonists on immediate early gene (IEG-like) responses in the prefrontal cortex. However, the OX2 receptor antagonist LSN2424100 did suppress restraint stress-induced increases in c-Fos protein expression without having any effects on baseline Fos protein expression in the home cage [90]. These effects of the OX2 receptor antagonist LSN2424100 on restraint stress-induced increases Fos expression in the prelimbic cortex are similar to an effect of the mGlu2 receptor agonist LY354740 on restraint stress-induced increases in Fos expression [45]. As discussed above, 5-HT2A receptor agonists induce a number of immediate IEG-like responses in the prefrontal cortex. Activation of mGlu2 receptors appears to suppress the DOI-induced increases in a

Modulation of 5-HT2A receptor agonist-induced head twitches is a behavioral measure that is suppressed by a range of antidepressants blocking/regulating 5-HT2A receptors as discussed above; these DOI-induced head twitches are also suppressed by the selective OX2 receptor antagonist LSN2424100 (**Figure 1**). LSN2424100 possesses approximately 200-fold functional OX2 receptor antagonist activity at both human recombinant OX2 vs. OX1 receptors or rat OX2 vs. OX1

antidepressant medication.

alcohol and drug self-administration, stress, anxiety and depression models [83]. The involvement of OX2 receptors in arousal together with the presence of OX2 receptor mRNA in the non-specific midline and intralaminar thalamic nuclei and the interactions of the orexin system with brainstem nuclei with overlapping monoamine projections makes the OX2 receptor an especially interesting target for mood disorder therapeutics [78, 83]. As discussed below, OX2 or hypocretin-2 receptor blockade appears to be a mechanism of action that provides a means of testing the hypothesis discussed above where a drug appropriately modifying multiple levels of biological effects for 5-HT2A receptor activation in the mPFC would be a putative

Electrophysiological effects of OX2 receptor activation in the prefrontal cortex appear to parallel certain effects of 5-HT2A receptor activation when recording from layer V pyramidal neurons. The orexin-B (hypocretin-2) peptide was found to increase spontaneous EPSC/EPSPs in layer V pyramidal neurons of the prefrontal cortex that were blocked by postsynaptic AMPA receptor antagonists as well as by TTX and u-opioid agonists on the presynaptic side similar to the case for 5-HT2A receptor stimulation [84]. Experiments to delineate the origin of afferents in the PFC from which orexin induced glutamate release from suggested that the cells of origin were in the midline and intralaminar thalamic nuclei [84]. Further, the relative potency for orexin-B compared to orexin-A (hypocretin-1) at inducing spontaneous OX-induced EPSCs/EPSPs in PFC layer V pyramidal cells is similar to that found in the intralaminar and midline thalamic nuclei with OX2, not OX1, receptor responses [84–86]. The tetrodotoxin sensitivity of the orexin-induced EPSCs/ EPSPs is in keeping with earlier studies suggesting that thalamocortical projections from these "non-specific" thalamic nuclei associated with arousal were prone to the generation of terminal spikes as previously suggested [87, 88]. This dependence on thalamocortical pathways originating in the midline and intralaminar thalamic nuclei and terminating in layers I and Va of the prefrontal cortex is consistent with features for the spontaneous 5-HT-induced EPSCs/EPSPs [26, 27]. One difference between OX-induced spontaneous EPSCs and 5-HT-induced EPSCS is that OX does not appear to induce postsynaptic depolarization (consistent with absence of OX2 mRNA in layer V pyramidal cells) unlike the case for 5-HT2A receptor activation in the majority of layer V pyramidal cells [84, 89]. However, studies characterizing the ability of orexin-B induced EPSCs/EPSPs to be blocked with selective OX2 receptor antagonists or selective OX1 receptor antagonists would be useful to unambiguously

**88**

*The effect of (±)-DOI (3 mg/kg, i.p.) and the selective OX2 receptor antagonist LSN2424100 (10 mg/kg, i.p.) on head twitches in CD-1 wild-type mice observed for 30 min following drug administration. LSN2424100 was administered 30 min prior to DOI. Each bar represents the mean (± SEM) of eight mice. Significantly different from the mean number of head twitches for the vehicle/DOI group, \* p < 0.05. Significantly different from the number of mice displaying head twitches for the vehicle/DOI group, # p < 0.05 by the Fisher exact test.*

#### **Figure 2.**

*The antidepressant-like effect of LSN2424100 on male Sprague-Dawley rats (n = 7) stably performing under a DRL 72-s schedule. The top graph shows the effects of LSN2424100 (3–30 mg, i.p.) and imipramine (10 mg/ kg, i.p.) on the number of reinforcers obtained after vehicle/drug was administered 1 hour prior to the daily session. The bottom graph shows the effect of LSN2424100 (3–30 mg, i.p.) and imipramine (10 mg/kg, i.p.) on the total number of responses. The dotted line shows the control reinforcement and response rate and \* denotes data points significantly different from control (p < 0.05) (this figure was adapted from data presented by Fitch et al. [90]).*

were observed in OX2 receptor knockout mice when testing LSN2424100 doses up to twice as large as those used for wild-type and OX1 receptor knockout mice [90]. A similar antidepressant-like profile was observed in rats, wild-type CD-1 mice, and OX1 receptor KO mice with the non-selective OX1/OX2 receptor antagonist almorexant [90]. In contrast, a selective OX1 receptor antagonist failed to produce an antidepressant-like response in rats performing on a DRL 72-s schedule or wild type mice or OX2 receptor knockout mice responding on a DRL 36-s schedule [90]. However, the well-established tricyclic antidepressant drug imipramine tested as expected in these experiments as a positive control (e.g., antidepressant-like effects) in Sprague-Dawley rats, wild-type mice, OX1 receptor knockout mice, or OX2 receptor KO mice trained to lever press under a DRL 72-s schedule (rats) or a DRL 36-s (mice) schedule.

#### **3. Clinical trials with orexin receptor antagonists in patients with MDD**

**91**

trial as well [81].

*Orexin 2 Receptor Antagonists from Prefrontal Cortical Circuitry to Rodent Behavioral Screens*

Only 47 men and women with a diagnosis of MDD (DSM-IV) were randomized to received either diphenhydramine, 25 mg q.d. (n = 13), seltorexant, 20 mg q.d. (n = 22) or placebo (n = 12) for 10 nights. Sleep polysomnography was also performed to provide objective assessment of improvements on sleep. There were improvements from baseline in the seltorexant treatment group for the HAMD-17 total score (−3.6 points) as well as the HAM-17 adjusted total score accounting for sleep improvement in addition to changes in the HAMD-6 item score (−1.5 points). This resulted in effect sizes of −0.48, −0.55 and − 1.05 for the OX2 receptor antagonist compared to placebo. However, one caveat is that the subjects assigned to the histamine H1 receptor antagonist diphenhydramine showed highly comparable improvement compared to placebo as did seltorexant. To answer these questions/ concerns, a phase 2b randomized, double-blind parallel group, placebo-controlled, adaptive dose-finding trial for seltorexant adjunctive treatment to antidepressants scheduled to enroll about 280 adult subjects at 85 US, European, Russian and

The only other MDD clinical trial for an OX receptor antagonist was negative [95]. Filorexant (MK-6096), a dual orexin receptor antagonist, was evaluated in a 6-week, double-blind, placebo-controlled, parallel-group phase 2a proof-of-concept trial where subjects with MDD were randomized 1:1 to once-daily oral filorexant 10 mg or matching placebo. Subjects on antidepressants continued to take their prescribed antidepressant for the duration of the trial. This study was stopped after enrolling 129 (40%) of a planned 326 subjects. Less than a 1 point numerical improvement was observed for filorexant compared to placebo using the mean change from baseline to week 6 MADRS total score. Exploratory analyses also failed to reveal statistically significant changes in the Insomnia Severity Index (ISI). Regarding safety, there were no deaths, drug-related serious adverse events (SAEs) and only one discontinuation due to AEs in both treatment groups. There were no

This negative filorexant MDD study may be related to an issue of inadequate power as the planned study was designed with 80% power to detect a 3.5-point difference between treatments with a 2-sided 5% level of significance and a fully enrolled trial. However, the enrollment of only 129 subjects while using 61 sites (United States, Canada, Finland, France, Germany, Norway and Sweden) speaks to the recruitment challenges in this study. The dose chosen for this MDD trial appears reasonable based on positive effects reported for filorexant in a phase 2 randomized, double-blind, placebo-controlled adaptive crossover polysomnography dose-ranging study evaluating approximately 80 subjects each at nightly doses of 2.5, 5 and 10 mg [81]. All doses showed significant effects on sleep efficiency and wakefulness after persistent sleep onset while the two higher doses demonstrated significant effects on sleep onset. Filorexant was also well tolerated in this insomnia

Preclinical results suggest that the combined OX1/OX2 receptor antagonism should not have compromised potential antidepressant action in patients with MDD. Namely, the OX1/OX2 receptor antagonist almorexant acted similarly to the OX2 receptor antagonist LSN2424100 and the known tricyclic antidepressant imipramine in rats and mice performing on DRL 72-s or DRL 36-s schedules [90]. In addition, the non-selective OX receptor antagonist almorexant also tested similarly to known antidepressants in mice subjected to unpredictable chronic mild stress (UCMS) and then evaluated with the tail suspension test, the resident-intruder test, and the elevated plus maze [96]. However, opposing antidepressant-like and "pro-depressant"-like effects were observed in OX1 and OX2 receptor knockout mice, respectively, studied with the forced swim paradigm [97]. In this same study, the selective OX1 receptor antagonist SB-334867 also exerted an antidepressant like

*DOI: http://dx.doi.org/10.5772/intechopen.82544*

Japanese sites began in September 2017 (NCT03227224).

other problematic safety issues reported.

Thus far only a single small double-blind, placebo-controlled, diphenhydramine-controlled, parallel group, phase 1b/2a trial of a selective OX2 receptor antagonist, JNJ-42847922/MIN-202 or seltorexant, has been conducted [94].

#### *Orexin 2 Receptor Antagonists from Prefrontal Cortical Circuitry to Rodent Behavioral Screens DOI: http://dx.doi.org/10.5772/intechopen.82544*

Only 47 men and women with a diagnosis of MDD (DSM-IV) were randomized to received either diphenhydramine, 25 mg q.d. (n = 13), seltorexant, 20 mg q.d. (n = 22) or placebo (n = 12) for 10 nights. Sleep polysomnography was also performed to provide objective assessment of improvements on sleep. There were improvements from baseline in the seltorexant treatment group for the HAMD-17 total score (−3.6 points) as well as the HAM-17 adjusted total score accounting for sleep improvement in addition to changes in the HAMD-6 item score (−1.5 points). This resulted in effect sizes of −0.48, −0.55 and − 1.05 for the OX2 receptor antagonist compared to placebo. However, one caveat is that the subjects assigned to the histamine H1 receptor antagonist diphenhydramine showed highly comparable improvement compared to placebo as did seltorexant. To answer these questions/ concerns, a phase 2b randomized, double-blind parallel group, placebo-controlled, adaptive dose-finding trial for seltorexant adjunctive treatment to antidepressants scheduled to enroll about 280 adult subjects at 85 US, European, Russian and Japanese sites began in September 2017 (NCT03227224).

The only other MDD clinical trial for an OX receptor antagonist was negative [95]. Filorexant (MK-6096), a dual orexin receptor antagonist, was evaluated in a 6-week, double-blind, placebo-controlled, parallel-group phase 2a proof-of-concept trial where subjects with MDD were randomized 1:1 to once-daily oral filorexant 10 mg or matching placebo. Subjects on antidepressants continued to take their prescribed antidepressant for the duration of the trial. This study was stopped after enrolling 129 (40%) of a planned 326 subjects. Less than a 1 point numerical improvement was observed for filorexant compared to placebo using the mean change from baseline to week 6 MADRS total score. Exploratory analyses also failed to reveal statistically significant changes in the Insomnia Severity Index (ISI). Regarding safety, there were no deaths, drug-related serious adverse events (SAEs) and only one discontinuation due to AEs in both treatment groups. There were no other problematic safety issues reported.

This negative filorexant MDD study may be related to an issue of inadequate power as the planned study was designed with 80% power to detect a 3.5-point difference between treatments with a 2-sided 5% level of significance and a fully enrolled trial. However, the enrollment of only 129 subjects while using 61 sites (United States, Canada, Finland, France, Germany, Norway and Sweden) speaks to the recruitment challenges in this study. The dose chosen for this MDD trial appears reasonable based on positive effects reported for filorexant in a phase 2 randomized, double-blind, placebo-controlled adaptive crossover polysomnography dose-ranging study evaluating approximately 80 subjects each at nightly doses of 2.5, 5 and 10 mg [81]. All doses showed significant effects on sleep efficiency and wakefulness after persistent sleep onset while the two higher doses demonstrated significant effects on sleep onset. Filorexant was also well tolerated in this insomnia trial as well [81].

Preclinical results suggest that the combined OX1/OX2 receptor antagonism should not have compromised potential antidepressant action in patients with MDD. Namely, the OX1/OX2 receptor antagonist almorexant acted similarly to the OX2 receptor antagonist LSN2424100 and the known tricyclic antidepressant imipramine in rats and mice performing on DRL 72-s or DRL 36-s schedules [90]. In addition, the non-selective OX receptor antagonist almorexant also tested similarly to known antidepressants in mice subjected to unpredictable chronic mild stress (UCMS) and then evaluated with the tail suspension test, the resident-intruder test, and the elevated plus maze [96]. However, opposing antidepressant-like and "pro-depressant"-like effects were observed in OX1 and OX2 receptor knockout mice, respectively, studied with the forced swim paradigm [97]. In this same study, the selective OX1 receptor antagonist SB-334867 also exerted an antidepressant like

*Antidepressants - Preclinical, Clinical and Translational Aspects*

were observed in OX2 receptor knockout mice when testing LSN2424100 doses up to twice as large as those used for wild-type and OX1 receptor knockout mice [90]. A similar antidepressant-like profile was observed in rats, wild-type CD-1 mice, and OX1 receptor KO mice with the non-selective OX1/OX2 receptor antagonist almorexant [90]. In contrast, a selective OX1 receptor antagonist failed to produce an antidepressant-like response in rats performing on a DRL 72-s schedule or wild type mice or OX2 receptor knockout mice responding on a DRL 36-s schedule [90]. However, the well-established tricyclic antidepressant drug imipramine tested as expected in these experiments as a positive control (e.g., antidepressant-like effects) in Sprague-Dawley rats, wild-type mice, OX1 receptor knockout mice, or OX2 receptor KO mice trained to

*The antidepressant-like effect of LSN2424100 on male Sprague-Dawley rats (n = 7) stably performing under a DRL 72-s schedule. The top graph shows the effects of LSN2424100 (3–30 mg, i.p.) and imipramine (10 mg/ kg, i.p.) on the number of reinforcers obtained after vehicle/drug was administered 1 hour prior to the daily session. The bottom graph shows the effect of LSN2424100 (3–30 mg, i.p.) and imipramine (10 mg/kg, i.p.) on the total number of responses. The dotted line shows the control reinforcement and response rate and \* denotes data points significantly different from control (p < 0.05) (this figure was adapted from data presented by Fitch* 

lever press under a DRL 72-s schedule (rats) or a DRL 36-s (mice) schedule.

**3. Clinical trials with orexin receptor antagonists in patients with MDD**

Thus far only a single small double-blind, placebo-controlled, diphenhydramine-controlled, parallel group, phase 1b/2a trial of a selective OX2 receptor antagonist, JNJ-42847922/MIN-202 or seltorexant, has been conducted [94].

**90**

**Figure 2.**

*et al. [90]).*

effect in the forced swim test. No data has been published suggesting that selective OX2 receptor antagonists test as antidepressants in rodent forced swim tests. Nevertheless, the balance of data are consistent with the hypothesis that adequate blockade of both OX1 and OX2 receptors, or OX2 receptors alone, should improve depressive symptoms in patients with MDD.

#### **4. Conclusions**

Activation of 5-HT2A receptors or OX2 receptors appears to induce glutamate release from thalamocortical terminals with cell bodies originating in the midline and intralaminar thalamic nuclei when recording from prefrontal cortical layer V pyramidal neurons (**Figure 3**). This 5-HT and orexin-B-induced glutamate release appears to dependent action potentials in the presynaptic terminals judging from the TTX-induced blockade of the 5-HT- or orexin-induced EPSC/EPSPs as

#### **Figure 3.**

*The model where activation of 5-HT2A or OX2 receptors depolarizes and releases glutamate from non-specific thalamocortical inputs to layer I and Va of the apical dendrites from layer V pyramidal neurons. The majority of 5-HT2A receptors, apart from a minority of presynaptic receptors and those on GABAergic interneurons, are present on and also directly depolarize layer V pyramidal neurons. Other glutamatergic receptors (mGlu2 and mGlu4), μ-opioid receptors and adenosine A1 receptors that suppress the EPSCs/EPSPs induced by activation of 5-HT2A and OX2 receptors appear to be present on non-specific thalamocortical afferents. This circuitry (with additional positive modulator receptor such as mGlu5 and NK3 receptors and also additional negative modulators such as β2-adrenergic receptors) appears to underlie a similar valence of action for all these receptors for a behavior mediated by activation of 5-HT2A receptors in the prefrontal cortex, DOI-induced head twitches. This circuitry also appears to underlie impulsive behavior (DRL 72-s behavior) where a similar valence of GPCR mediated effects appears to drive antidepressant-like effects on this screening behavior as DOI-induced head twitches and 5-HT-induced EPSCs.*

**93**

*Orexin 2 Receptor Antagonists from Prefrontal Cortical Circuitry to Rodent Behavioral Screens*

suggested previously for non-specific thalamocortical axons. Apical dendritic layer V pyramidal AMPA receptors appear to be activated postsynaptic to the thalamic terminals. The 5-HT or DOI-induced spontaneous EPSCs/EPSPs or DOI/electrically evoked EPSC/EPSPs also appear suppressed by mGlu2, mGlu4, adenosine A1, 5-HT-1-like

Future work is required to establish that orexin-B-induced glutamate release from non-specific thalamic afferents is also suppressed by mGlu2, mGlu4, adenosine A1, 5-HT-1-like and β2-adrenergic receptors. Blockade of OX2 and 5-HT2A receptors also both appear to suppress DOI-induced head twitches, a behavioral response that appears to be mediated by activation of prefrontal cortical 5-HT2A receptors. A selective OX2 receptor antagonist tested similar to the tricyclic antidepressant imipramine in rats and mice responding under an operant DRL 72-s schedule of reinforcement. Another question for future preclinical research with rodent DRL behavior is whether blockade of OX2 receptors is additive/synergistic with tricyclic antidepressants or SSRIs in the same manner as blockade of 5-HT2A receptors. The ongoing clinical antidepressant trial with the OX2 receptor antagonist seltorexant are important to understanding whether the circuitry involving orexin-containing cells in the hypothalamus together with orexin-containing axon terminals in the intralaminar and midline thalamic nuclei and the prefrontal cortex are necessary and sufficient by themselves to augment the antidepressant effects of tricyclic antidepressants and SSRIs. If this ongoing and other clinical antidepressant trials with selective OX2 receptor antagonists or additional adequately powered clinical trials testing OX1/OX2 receptor antagonists are negative, then future work will be required to begin to ask whether additional actions of OX2 receptor antagonists in other circuitry are functionally opposed to the brainstem/thalamic/prefrontal

The present manuscript was not supported by either Astellas or Lundbeck.

The authors were previously employed by Eli Lilly.

*DOI: http://dx.doi.org/10.5772/intechopen.82544*

and β2-adrenergic receptors.

cortical circuits.

**Acknowledgements**

**Conflict of interest**

*Orexin 2 Receptor Antagonists from Prefrontal Cortical Circuitry to Rodent Behavioral Screens DOI: http://dx.doi.org/10.5772/intechopen.82544*

suggested previously for non-specific thalamocortical axons. Apical dendritic layer V pyramidal AMPA receptors appear to be activated postsynaptic to the thalamic terminals. The 5-HT or DOI-induced spontaneous EPSCs/EPSPs or DOI/electrically evoked EPSC/EPSPs also appear suppressed by mGlu2, mGlu4, adenosine A1, 5-HT-1-like and β2-adrenergic receptors.

Future work is required to establish that orexin-B-induced glutamate release from non-specific thalamic afferents is also suppressed by mGlu2, mGlu4, adenosine A1, 5-HT-1-like and β2-adrenergic receptors. Blockade of OX2 and 5-HT2A receptors also both appear to suppress DOI-induced head twitches, a behavioral response that appears to be mediated by activation of prefrontal cortical 5-HT2A receptors. A selective OX2 receptor antagonist tested similar to the tricyclic antidepressant imipramine in rats and mice responding under an operant DRL 72-s schedule of reinforcement. Another question for future preclinical research with rodent DRL behavior is whether blockade of OX2 receptors is additive/synergistic with tricyclic antidepressants or SSRIs in the same manner as blockade of 5-HT2A receptors. The ongoing clinical antidepressant trial with the OX2 receptor antagonist seltorexant are important to understanding whether the circuitry involving orexin-containing cells in the hypothalamus together with orexin-containing axon terminals in the intralaminar and midline thalamic nuclei and the prefrontal cortex are necessary and sufficient by themselves to augment the antidepressant effects of tricyclic antidepressants and SSRIs. If this ongoing and other clinical antidepressant trials with selective OX2 receptor antagonists or additional adequately powered clinical trials testing OX1/OX2 receptor antagonists are negative, then future work will be required to begin to ask whether additional actions of OX2 receptor antagonists in other circuitry are functionally opposed to the brainstem/thalamic/prefrontal cortical circuits.

#### **Acknowledgements**

*Antidepressants - Preclinical, Clinical and Translational Aspects*

depressive symptoms in patients with MDD.

**4. Conclusions**

effect in the forced swim test. No data has been published suggesting that selective OX2 receptor antagonists test as antidepressants in rodent forced swim tests. Nevertheless, the balance of data are consistent with the hypothesis that adequate blockade of both OX1 and OX2 receptors, or OX2 receptors alone, should improve

Activation of 5-HT2A receptors or OX2 receptors appears to induce glutamate release from thalamocortical terminals with cell bodies originating in the midline and intralaminar thalamic nuclei when recording from prefrontal cortical layer V pyramidal neurons (**Figure 3**). This 5-HT and orexin-B-induced glutamate release appears to dependent action potentials in the presynaptic terminals judging from the TTX-induced blockade of the 5-HT- or orexin-induced EPSC/EPSPs as

**92**

*DOI-induced head twitches and 5-HT-induced EPSCs.*

**Figure 3.**

*The model where activation of 5-HT2A or OX2 receptors depolarizes and releases glutamate from non-specific thalamocortical inputs to layer I and Va of the apical dendrites from layer V pyramidal neurons. The majority of 5-HT2A receptors, apart from a minority of presynaptic receptors and those on GABAergic interneurons, are present on and also directly depolarize layer V pyramidal neurons. Other glutamatergic receptors (mGlu2 and mGlu4), μ-opioid receptors and adenosine A1 receptors that suppress the EPSCs/EPSPs induced by activation of 5-HT2A and OX2 receptors appear to be present on non-specific thalamocortical afferents. This circuitry (with additional positive modulator receptor such as mGlu5 and NK3 receptors and also additional negative modulators such as β2-adrenergic receptors) appears to underlie a similar valence of action for all these receptors for a behavior mediated by activation of 5-HT2A receptors in the prefrontal cortex, DOI-induced head twitches. This circuitry also appears to underlie impulsive behavior (DRL 72-s behavior) where a similar valence of GPCR mediated effects appears to drive antidepressant-like effects on this screening behavior as* 

The present manuscript was not supported by either Astellas or Lundbeck.

#### **Conflict of interest**

The authors were previously employed by Eli Lilly.

#### **Author details**

Gerard J. Marek1 \*, Stephen Chaney2 and Mark J. Benvenga<sup>3</sup>

1 Astellas Pharma Global Development Inc., Northbrook, IL, USA

2 Eli Lily Research Laboratories, Indianapolis, IN, USA

3 Lundbeck, Sacramento, CA, USA

\*Address all correspondence to: gerard.marek@astellas.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**95**

*Orexin 2 Receptor Antagonists from Prefrontal Cortical Circuitry to Rodent Behavioral Screens*

[8] Blier P, Gobbi G, Turcotte JE, de Montigny C, Boucher N, Hebert C, et al. Mirtazapine and paroxetine in major depression: A comparison of monotherapy versus their combination from treatment initiation. European

[9] Carpenter LL, Yasmin S, Price LH. A double-blind placebo-controlled study of antidepressant augmentation with mirtazapine. Biological Psychiatry.

[10] Ferreri M, Lavergne F, Berlin I, Payan C, Peuch AJ. Benefits from mianserin augmentation of fluoxetine in patients with major depression non-responders to fluoxetine alone. Acta Psychiatrica Scandinavica.

[11] Han C, Wang S-M, Kato M, Lee S-J, Patkar AA, Masand PS, et al. Second-generation antipsychotics in the treatment of major depressive disorder: Current evidence. Expert Review of Neurotherapeutics. 2013;**13**:851-874

[12] Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorders: A meta-analysis of placebo-controlled randomized trials. The American Journal of Psychiatry.

Neuropsychopharmacology.

2009;**19**:457-465

2002;**51**:183-188

2001;**103**:66-72

2009;**166**:980-991

2003;**28**:402-412

[13] Marek GJ, Carpenter LL, McDougle CJ, Price LH. Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors

in neuropsychiatric disorders. Neuropsychopharmacology.

[14] Marek GJ. Regulation of rat cortical 5-hydroxytryptamine2A-receptor mediated electrophysiological responses

by repeated daily treatment with electroconvulsive shock or imipramine.

*DOI: http://dx.doi.org/10.5772/intechopen.82544*

[1] Bradley AJ, Lenox-Smith AJ. Does adding noradrenaline reuptake inhibition to selective serotonin

reuptake inhibition improve efficacy in patients with depression? A systematic review of meta-analysis and large randomized pragmatic trials. Journal of psychopharmacology (Oxford, England). 2013;**27**:740-758

[2] Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: A multiple-treatments meta-analysis.

Lancet. 2009;**373**:746-758

2010;**11**:300-307

2005;**20**:533-539

2008;**111**:46-51

2005;**89**:125-135

Anxiety. 2001;**14**:19-28

[4] Mayers AG, Baldwin

DS. Antidepressants and their effect on sleep. Human Psychopharmacology.

[5] Nakano Y, Baba H, Maeshima H, Kitajima A, Sakai Y, Baba K, et al. Executive dysfunction in medicated, remitted state of major depression. Journal of Affective Disorders.

[6] Paelecke-Habermann Y, Pohl J, Leplow B. Attention and executive function in remitted major depression patients. Journal of Affective Disorders.

[7] Winokur A, Gary KA, Rodner S, Rae-Red C, Fernando AT, Szuba MP. Depression, sleep physiology, and antidepressant drugs. Depression and

[3] Papakostas GI, Charles D, Fava M. Are typical starting doses of the selective serotonin reuptake inhibitors sub-optimal? A meta-analysis of randomized, double-blind, placebocontrolled, dose-finding studies in major depressive disorder. The World Journal of Biological Psychiatry.

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*Orexin 2 Receptor Antagonists from Prefrontal Cortical Circuitry to Rodent Behavioral Screens DOI: http://dx.doi.org/10.5772/intechopen.82544*

#### **References**

*Antidepressants - Preclinical, Clinical and Translational Aspects*

**94**

**Author details**

Gerard J. Marek1

provided the original work is properly cited.

3 Lundbeck, Sacramento, CA, USA

\*, Stephen Chaney2

2 Eli Lily Research Laboratories, Indianapolis, IN, USA

\*Address all correspondence to: gerard.marek@astellas.com

1 Astellas Pharma Global Development Inc., Northbrook, IL, USA

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

and Mark J. Benvenga<sup>3</sup>

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[2] Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: A multiple-treatments meta-analysis. Lancet. 2009;**373**:746-758

[3] Papakostas GI, Charles D, Fava M. Are typical starting doses of the selective serotonin reuptake inhibitors sub-optimal? A meta-analysis of randomized, double-blind, placebocontrolled, dose-finding studies in major depressive disorder. The World Journal of Biological Psychiatry. 2010;**11**:300-307

[4] Mayers AG, Baldwin DS. Antidepressants and their effect on sleep. Human Psychopharmacology. 2005;**20**:533-539

[5] Nakano Y, Baba H, Maeshima H, Kitajima A, Sakai Y, Baba K, et al. Executive dysfunction in medicated, remitted state of major depression. Journal of Affective Disorders. 2008;**111**:46-51

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[7] Winokur A, Gary KA, Rodner S, Rae-Red C, Fernando AT, Szuba MP. Depression, sleep physiology, and antidepressant drugs. Depression and Anxiety. 2001;**14**:19-28

[8] Blier P, Gobbi G, Turcotte JE, de Montigny C, Boucher N, Hebert C, et al. Mirtazapine and paroxetine in major depression: A comparison of monotherapy versus their combination from treatment initiation. European Neuropsychopharmacology. 2009;**19**:457-465

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[10] Ferreri M, Lavergne F, Berlin I, Payan C, Peuch AJ. Benefits from mianserin augmentation of fluoxetine in patients with major depression non-responders to fluoxetine alone. Acta Psychiatrica Scandinavica. 2001;**103**:66-72

[11] Han C, Wang S-M, Kato M, Lee S-J, Patkar AA, Masand PS, et al. Second-generation antipsychotics in the treatment of major depressive disorder: Current evidence. Expert Review of Neurotherapeutics. 2013;**13**:851-874

[12] Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorders: A meta-analysis of placebo-controlled randomized trials. The American Journal of Psychiatry. 2009;**166**:980-991

[13] Marek GJ, Carpenter LL, McDougle CJ, Price LH. Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology. 2003;**28**:402-412

[14] Marek GJ. Regulation of rat cortical 5-hydroxytryptamine2A-receptor mediated electrophysiological responses by repeated daily treatment with electroconvulsive shock or imipramine.

European Neuropsychopharmacology. 2008;**18**:498-507

[15] Marek GJ. Cortical 5-hydroxytryptamine2A-receptor mediated excitatory synaptic currents in the rat following repeated daily fluoxetine administration. Neuroscience Letters. 2008;**438**:312-316

[16] DUAG. Citalopram: Clinical effect profile in comparison with clomipramine—A controlled multicenter study. Psychopharmacology. 1986;**90**:131-138

[17] DUAG. Paroxetine: A selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. Journal of Affective Disorders. 1990;**18**:289-299

[18] Drevets WC. Functional neuroimaging studies of depression: The anatomy of melancholia. Annual Review of Medicine. 1998;**49**:341-361

[19] Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME. A functional anatomical study of unipolar depression. Journal of Neuroscience. 1992;**12**:3628-3641

[20] Mayberg HS. Limbic-cortical dysregulation: A proposed model of depression. Journal of Neuropsychiatry & Clinical Neurosciences. 1997;**9**(3):471-481

[21] Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY, et al. Morphometric evidence for neuronal and glia prefrontal cell pathology in major depression. Biological Psychiatry. 1999;**45**:1085-1098

[22] Price JL. Prefrontal cortical networks related to visceral function and mood. Annuals of New York Academy of Sciences. 1999;**877**:383

[23] Price JL, Drevets WC. Neurocircuitry of mood disorders. Neuropsychopharmacology. 2010;**35**:192-216

[24] Aghajanian GK, Marek GJ. Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells. Neuropharmacology. 1997;**36**(3/4):589-599

[25] Zhang C, Marek GJ. AMPA receptors involvement in 5-hydroxytryptamine2A receptor-mediated prefrontal cortical excitatory synaptic currents and DOIinduced head shakes. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2008;**32**:62-71

[26] Lambe EK, Aghajanian GK. The role of Kv1.2-containing potassium channels in serotonin-induced glutamate release from thalamocortical terminals in rat frontal cortex. The Journal of Neuroscience. 2001;**21**:9955-9963

[27] Marek GJ, Wright RA, Gewirtz JC, Schoepp DD. A major role for thalamocortical afferents in serotonergic hallucinogen receptor function in the rat neocortex. Neuroscience. 2001;**105**:379-392

[28] Benneyworth MA, Xiang Z, Smith RL, Garcia EE, Conn PJ, Sanders-Bush E. A selective positive allosteric modulator of metabotropic glutamate receptor subtype 2 blocks a hallucinogenic drug model of psychosis. Molecular Pharmacology. 2007;**72**:477-484

[29] Marek GJ, Aghajanian GK. 5-HT-induced EPSCs in neocortical layer V pyramidal cells: Suppression by μ-opiate receptor activation. Neuroscience. 1998;**86**:485-497

[30] Marek GJ, Wright RA, Schoepp DD, Monn JA, Aghajanian GK. Physiological antagonism between 5-hydroxytryptamine2A and group

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System: Permissive Network Effects Mediated through Cortical Layer V Pyramidal Neurons. Current Topics in Behavioral Neuroscience. Berlin,

Heidelberg: Springer; 2017

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[39] Lambe EK, Aghajanian

Behavior. 2002;**73**:317-326

2007;**53**:439-452

1999;**825**:161-171

2006;**31**:1682-1689

receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release. Brain Research.

GK. Hallucinogen-induced UP states in the brain slice rat prefrontal cortex: Role of glutamate spillover and NR2B-NMDA receptors. Neuropsychopharmacology.

[40] Gewirtz JC, Chen AC, Terwilliger R, Duman RC, Marek GJ. Modulation of DOI-induced increases in cortical BDNF expression by group II mGlu receptors. Pharmacology, Biochemistry, and

[41] Gonzalez-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, Lopez-Gimenez JF, et al. Identification of a serotonin/ glutamate receptor complex implicated in psychosis. Nature. 2008;**452**:93-97

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[43] Scruggs JL, Patel S, Bubser M, Deutch AY. DOI-induced activation of the cortex: Dependence upon 5-HT2A heteroceptors on thalamocortical glutamatergic neurons. The Journal of Neuroscience. 2000;**20**:8846-8852

[44] Wischhof L, Koch M. Pretreatment

with the mGlu2/3 receptor agonist LY379268 attenuates DOIinduced impulsive responding and

*DOI: http://dx.doi.org/10.5772/intechopen.82544*

[32] Stutzman GE, Marek GJ, Aghajanian GK. Adenosine preferentially suppresses

excitatory postsynaptic currents in layer V neurons of the rat medial prefrontal cortex. Neuroscience. 2001;**105**:55-69

serotonin2A receptor-enhanced

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[34] Marek GJ, Zhang C. Activation of metabotropic glutamate 5 (mGlu5) receptors induces spontaneous excitatory synaptic currents in layer V pyramidal cells of the rat prefrontal

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[36] Marek GJ, Aghajanian GK. The electrophysiology of prefrontal 5-HT systems: Therapeutic implications for mood and psychosis. Biological Psychiatry. 1998;**44**:1118-1127

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Hallucinogens with the Glutamatergic

cortex. Neuroscience Letters.

2008;**442**:239-243

II metabotropic glutamate receptors in prefrontal cortex. The Journal of Pharmacology and Experimental Therapeutics. 2000;**292**:76-87

[31] Slawinska A, Wieronska JM, Stachowicz K, Marciniak M, Lason-Tyburkiewicz M, Gruca P, et al. The antipsychotic-like effects of positive allosteric modulators of metabotropic glutamate mGlu4 receptors in rodents. British Journal of Pharmacology.

2013;**169**:1824-1839

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II metabotropic glutamate receptors in prefrontal cortex. The Journal of Pharmacology and Experimental Therapeutics. 2000;**292**:76-87

[31] Slawinska A, Wieronska JM, Stachowicz K, Marciniak M, Lason-Tyburkiewicz M, Gruca P, et al. The antipsychotic-like effects of positive allosteric modulators of metabotropic glutamate mGlu4 receptors in rodents. British Journal of Pharmacology. 2013;**169**:1824-1839

[32] Stutzman GE, Marek GJ, Aghajanian GK. Adenosine preferentially suppresses serotonin2A receptor-enhanced excitatory postsynaptic currents in layer V neurons of the rat medial prefrontal cortex. Neuroscience. 2001;**105**:55-69

[33] Zhang C, Marek GJ. Group III metabotropic glutamate receptor agonists selectively suppress excitatory synaptic currents in the rat prefrontal cortex induced by 5-hydroxytryptamine2A receptor stimulation. The Journal of Pharmacology and Experimental Therapeutics. 2007;**320**:437-447

[34] Marek GJ, Zhang C. Activation of metabotropic glutamate 5 (mGlu5) receptors induces spontaneous excitatory synaptic currents in layer V pyramidal cells of the rat prefrontal cortex. Neuroscience Letters. 2008;**442**:239-243

[35] Marek GJ, Aghajanian GK. 5-HT2A or α1-adrenoceptor activation induces excitatory postsynaptic currents in layer V pyramidal cells of the medial prefrontal cortex. European Journal of Pharmacology. 1999;**367**:197-206

[36] Marek GJ, Aghajanian GK. The electrophysiology of prefrontal 5-HT systems: Therapeutic implications for mood and psychosis. Biological Psychiatry. 1998;**44**:1118-1127

[37] Marek GJ. Interactions of Hallucinogens with the Glutamatergic System: Permissive Network Effects Mediated through Cortical Layer V Pyramidal Neurons. Current Topics in Behavioral Neuroscience. Berlin, Heidelberg: Springer; 2017

[38] Aghajanian GK, Marek GJ. Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release. Brain Research. 1999;**825**:161-171

[39] Lambe EK, Aghajanian GK. Hallucinogen-induced UP states in the brain slice rat prefrontal cortex: Role of glutamate spillover and NR2B-NMDA receptors. Neuropsychopharmacology. 2006;**31**:1682-1689

[40] Gewirtz JC, Chen AC, Terwilliger R, Duman RC, Marek GJ. Modulation of DOI-induced increases in cortical BDNF expression by group II mGlu receptors. Pharmacology, Biochemistry, and Behavior. 2002;**73**:317-326

[41] Gonzalez-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, Lopez-Gimenez JF, et al. Identification of a serotonin/ glutamate receptor complex implicated in psychosis. Nature. 2008;**452**:93-97

[42] Gonzalez-Maeso J, Weisstaub NV, Zhou M, Chan P, Ivic L, Ang R, et al. Hallucinogens recruit specific cortical 5-HT2A receptor-mediated signalling pathways to affect behavior. Neuron. 2007;**53**:439-452

[43] Scruggs JL, Patel S, Bubser M, Deutch AY. DOI-induced activation of the cortex: Dependence upon 5-HT2A heteroceptors on thalamocortical glutamatergic neurons. The Journal of Neuroscience. 2000;**20**:8846-8852

[44] Wischhof L, Koch M. Pretreatment with the mGlu2/3 receptor agonist LY379268 attenuates DOIinduced impulsive responding and

**96**

*Antidepressants - Preclinical, Clinical and Translational Aspects*

[23] Price JL, Drevets WC.

[24] Aghajanian GK, Marek GJ. Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal

cells. Neuropharmacology. 1997;**36**(3/4):589-599

Psychiatry. 2008;**32**:62-71

[25] Zhang C, Marek GJ. AMPA receptors involvement in 5-hydroxytryptamine2A receptor-mediated prefrontal cortical excitatory synaptic currents and DOIinduced head shakes. Progress in Neuro-Psychopharmacology & Biological

[26] Lambe EK, Aghajanian GK. The role of Kv1.2-containing potassium channels in serotonin-induced glutamate release from thalamocortical terminals in rat frontal cortex. The Journal of Neuroscience. 2001;**21**:9955-9963

[27] Marek GJ, Wright RA, Gewirtz JC, Schoepp DD. A major role for thalamocortical afferents in serotonergic hallucinogen receptor function in the rat neocortex. Neuroscience. 2001;**105**:379-392

[28] Benneyworth MA, Xiang Z, Smith RL, Garcia EE, Conn PJ, Sanders-Bush E. A selective positive allosteric modulator of metabotropic glutamate receptor subtype 2 blocks a hallucinogenic drug model of psychosis. Molecular Pharmacology.

[29] Marek GJ, Aghajanian GK. 5-HT-induced EPSCs in neocortical layer V pyramidal cells: Suppression by μ-opiate receptor activation. Neuroscience. 1998;**86**:485-497

[30] Marek GJ, Wright RA,

Schoepp DD, Monn JA, Aghajanian GK. Physiological antagonism between 5-hydroxytryptamine2A and group

2007;**72**:477-484

2010;**35**:192-216

Neurocircuitry of mood disorders. Neuropsychopharmacology.

European Neuropsychopharmacology.

5-hydroxytryptamine2A-receptor mediated excitatory synaptic currents in the rat following repeated daily fluoxetine administration. Neuroscience

[16] DUAG. Citalopram: Clinical effect profile in comparison with clomipramine—A controlled

[17] DUAG. Paroxetine: A selective serotonin reuptake inhibitor

showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. Journal of Affective Disorders.

neuroimaging studies of depression: The anatomy of melancholia. Annual Review

[19] Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME. A functional anatomical study of unipolar depression. Journal of Neuroscience. 1992;**12**:3628-3641

[20] Mayberg HS. Limbic-cortical dysregulation: A proposed model of depression. Journal of Neuropsychiatry

[21] Rajkowska G, Miguel-Hidalgo JJ,

& Clinical Neurosciences.

Wei J, Dilley G, Pittman SD, Meltzer HY, et al. Morphometric evidence for neuronal and glia prefrontal cell pathology in major depression. Biological Psychiatry.

[22] Price JL. Prefrontal cortical networks related to visceral function and mood. Annuals of New York Academy of Sciences. 1999;**877**:383

1997;**9**(3):471-481

1999;**45**:1085-1098

multicenter study. Psychopharmacology.

2008;**18**:498-507

1986;**90**:131-138

1990;**18**:289-299

[18] Drevets WC. Functional

of Medicine. 1998;**49**:341-361

[15] Marek GJ. Cortical

Letters. 2008;**438**:312-316

regional c-Fos protein expression. Psychopharmacology. 2012;**219**:387-400

[45] Menezes MM, Marek GJ, Benvenga MJ, Chaney S, Svensson KA. The mGlu2/3 receptor agonist LY354740 attenuates the restraint-stress induced Fos expression and DOI-induced Fos expression in prefrontal cortex. In: Neuroscience Meeting Planner Society for Neurocience. Chicago, IL: Society for Neuroscience; 2009. pp. 417-423

[46] Canal CE, Morgan D. Headtwitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4 iodoamphetamine: A comprehensive history, a re-evaluation of mechanisms, and its utility as a model. Drug Test Analysis. 2012;**4**:556-576

[47] Willins DL, Meltzer HY. Direct injection of 5-HT2A receptor agonists into the medial prefrontal cortex produces a head-twitch response in rats. The Journal of Pharmacology and Experimental Therapeutics. 1997;**282**:699-706

[48] Gewirtz JC, Marek GJ. Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors. Neuropsychopharmacology. 2000;**23**:569-576

[49] Klodzinska A, Bijak M, Tokarski K, Pilc A. Group II mGlu receptor agonists inhibit behavioral and electrophysiological effects of DOI in mice. Pharmacology Biochemistry & Behavior. 2002;**73**:327-332

[50] Marek GJ. Behavioral evidence for μ-opioid and 5-HT2A receptor interactions. European Journal of Pharmacology. 2003;**474**:77-83

[51] Marek GJ. Activation of adenosine1 receptors induces antidepressant-like, anti-impulsive effects on differential reinforcement of low-rate 72-s behavior in rats. The Journal of Pharmacology and Experimental Therapeutics. 2012;**341**:564-570

[52] Benvenga MJ, Chaney S, Baez M, Britton TC, Hornback WJ, Monn JA, et al. Metabotropic glutamate2 receptors play a key role in modulating head twitches induced by a serotonergic hallucinogen in mice. Frontiers in Pharmacology. 2018;**9**:208

[53] Rojoz Z. Effect of co-treatment with mirtazapine and risperidone in animal models of the positive symptoms of schizophrrenia in mice. Pharmacological Reports. 2012;**64**:1567-1572

[54] Blackshear MA, Sanders-Bush E. Serotonin receptor sensitivity after acute and chronic treatment with mianserin. The Journal of Pharmacology and Experimental Therapeutics. 1982;**221**:303-308

[55] Friedman E, Cooper TB, Dallob A. Effects of chronic antidepressant treatment on serotonin receptor activity in mice. European Journal of Pharmacology. 1983;**89**:69-76

[56] Maj J, Rogoz Z, Skuza G, Sowinska H. The effect of repeated administration of imipramine, citalopram and mianserin on responsiveness of central serotonergic, alpha 2-adrenergic and cholinergic system in mice. Polish Journal of Pharmacology and Pharmacy. 1989;**41**:313-319

[57] Ogren SO, Fuxe K, Agnati LF, Gustafsson JA, Jonsson G, Holm AC. Reevalulation of the indoleamine hypothesis of depression. Evidence for a reduction of functional activity of central 5-HT systems by antidepressant drugs. Journal of Neural Transmission. 1979;**46**:85-103

[58] Taylor DP, Carter RB, Eison AS, Mullins UL, Smith HL, Torrente JR, et al. Pharmacology and neurochemistry

**99**

1984;**83**:235-242

*Orexin 2 Receptor Antagonists from Prefrontal Cortical Circuitry to Rodent Behavioral Screens*

treatments. Journal of Neurochemistry.

[65] Pawlowski L, Ruczynska J, Gorka Z. Citalopram: A new potent inhibitor of serotonin (5-HT) uptake with central 5-HT-mimetic properties. Psychopharmacology. 1981;**74**:161-165

M. Inhibition of head twitch response

[67] Kawakami Y, Kitamura Y, Araki H, Kitagawa K, Suemaru K, Shibata K, et al. Effects of monoamine reuptake inhibitors on wet-dog shakes mediated by 5-HT2A receptors in ACTH-treated rats. Pharmacology, Biochemistry, and

[68] Kitamura Y, Araki H, Suemaru K, Gomita Y. Effects of imipramine and lithium on wet-dog shakes mediated by the 5-HT2A receptor in ACTH-treated rats. Pharmacology, Biochemistry, and

[69] Marek GJ, Day M, Hudzik TJ. The utility of impulsive bias and altered decision making as predictors of drug efficacy and target selection: Rethinking behavioral screening for antidepressant drugs. The Journal of Pharmacology and Experimental Therapeutics.

[70] O'Donnell JM, Marek GJ, Seiden LS. Antidepressant effects assessed using behavior maintained under a differential-reinforcement-of-low-rate (DRL) operant schedule. Neuroscience

and Biobehavioral Reviews.

[71] Marek GJ, Li AA, Seiden

antidepressant-like effects on

LS. Selective 5-hydroxytryptamine2

[66] Pawlowski L, Melzacka

to quipazine in rats by chronic amitriptyline but not fluvoxamine or citalopram. Psychopharmacology.

1988;**50**:730-738

1986;**88**:279-284

Behavior. 2005;**81**:65-70

Behavior. 2002;**72**:397-402

2016;**356**:534-548

2005;**29**:785-798

antagonists have

*DOI: http://dx.doi.org/10.5772/intechopen.82544*

of nefazodone, a novel antidepressant drug. Journal of Clinical Psychiatry.

[59] Clements-Jewery S, Robson PA, Chidley LJ. Biochemical investigations into the mode of action of trazodone. Neuropharmacology. 1980;**19**:1165-1173

[60] Cioli V, Corradino C, Piccinelli D, Rocchi MG, Valeri P. A comparative pharmacological study of trazodone, etoperidone and 1-(m-chlorophenyl) piperazine. Pharmacological Research Communications. 1984;**16**:85-100

[61] Nacca A, Guiso G, Fracasso C, Cervo L, Caccia S. Brain-to-blood partition and in vivo inhibition of 5-hydroxytryptamine reuptake and quipazine-mediated behaviour of nefazodone and its main active metabolites in rodents. British Journal of Pharmacology. 1998;**1998**:1617-1623

[62] Wettstein JG, Host M, Hitchcock JM. Selectivity of action of typical and atypical anti-psychotic drugs as antagonists of the behavioral effects of 1-[2,5-dimethoxy-4-iodophenyl]- 2-aminopropane (DOI). Progress in Neuro-Psychopharmacology & Biological Psychiatry. 1999;**23**:533-544

[63] Goodwin GM, Green AR, Johnson P. 5-HT2 receptor characteristics in frontal cortex and 5-HT2 receptormediated head-twitch behavior following antidepressant treatment to mice. British Journal of Pharmacology.

[64] Godfrey PP, McClue SJ, Young MM, Heal DJ. 5-hydroxytryptaminestimulated inositol phospholipid hydrolysis in the mouse cortex has pharmacological characteristics compatible with mediation via 5-HT2 receptors but this response does not reflect altered 5-HT2 function after 5,7-dihydroxytryptamine lesioning or repeated antidepressant

1995;**56**(Suppl 6):3-11

*Orexin 2 Receptor Antagonists from Prefrontal Cortical Circuitry to Rodent Behavioral Screens DOI: http://dx.doi.org/10.5772/intechopen.82544*

of nefazodone, a novel antidepressant drug. Journal of Clinical Psychiatry. 1995;**56**(Suppl 6):3-11

*Antidepressants - Preclinical, Clinical and Translational Aspects*

in rats. The Journal of Pharmacology and Experimental Therapeutics.

[52] Benvenga MJ, Chaney S, Baez M, Britton TC, Hornback WJ, Monn JA, et al. Metabotropic glutamate2 receptors play a key role in modulating head twitches induced by a serotonergic hallucinogen in mice. Frontiers in

[53] Rojoz Z. Effect of co-treatment with mirtazapine and risperidone in animal models of the positive symptoms of schizophrrenia in mice. Pharmacological

Pharmacology. 2018;**9**:208

Reports. 2012;**64**:1567-1572

[54] Blackshear MA, Sanders-Bush E. Serotonin receptor sensitivity after acute and chronic treatment with mianserin. The Journal of Pharmacology

and Experimental Therapeutics.

[55] Friedman E, Cooper TB, Dallob A. Effects of chronic antidepressant treatment on serotonin receptor activity in mice. European Journal of

[56] Maj J, Rogoz Z, Skuza G, Sowinska H. The effect of repeated administration

mianserin on responsiveness of central serotonergic, alpha 2-adrenergic and cholinergic system in mice. Polish Journal of Pharmacology and Pharmacy.

Pharmacology. 1983;**89**:69-76

of imipramine, citalopram and

[57] Ogren SO, Fuxe K, Agnati LF, Gustafsson JA, Jonsson G, Holm AC. Reevalulation of the indoleamine hypothesis of depression. Evidence for a reduction of functional activity of central 5-HT systems by antidepressant drugs. Journal of Neural Transmission.

[58] Taylor DP, Carter RB, Eison AS, Mullins UL, Smith HL, Torrente JR, et al. Pharmacology and neurochemistry

1982;**221**:303-308

1989;**41**:313-319

1979;**46**:85-103

2012;**341**:564-570

regional c-Fos protein expression. Psychopharmacology. 2012;**219**:387-400

Neuroscience; 2009. pp. 417-423

[46] Canal CE, Morgan D. Headtwitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4 iodoamphetamine: A comprehensive history, a re-evaluation of mechanisms, and its utility as a model. Drug Test

[47] Willins DL, Meltzer HY. Direct injection of 5-HT2A receptor agonists into the medial prefrontal cortex produces a head-twitch response in rats. The Journal of Pharmacology and Experimental Therapeutics.

[48] Gewirtz JC, Marek GJ. Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors. Neuropsychopharmacology.

[49] Klodzinska A, Bijak M, Tokarski K, Pilc A. Group II mGlu receptor agonists inhibit behavioral and electrophysiological effects of DOI in mice. Pharmacology Biochemistry &

[50] Marek GJ. Behavioral evidence for μ-opioid and 5-HT2A receptor interactions. European Journal of Pharmacology. 2003;**474**:77-83

[51] Marek GJ. Activation of adenosine1 receptors induces antidepressant-like, anti-impulsive effects on differential reinforcement of low-rate 72-s behavior

Behavior. 2002;**73**:327-332

Analysis. 2012;**4**:556-576

1997;**282**:699-706

2000;**23**:569-576

[45] Menezes MM, Marek GJ, Benvenga MJ, Chaney S, Svensson KA. The mGlu2/3 receptor agonist LY354740 attenuates the restraint-stress induced Fos expression and DOI-induced Fos expression in prefrontal cortex. In: Neuroscience Meeting Planner Society for Neurocience. Chicago, IL: Society for

**98**

[59] Clements-Jewery S, Robson PA, Chidley LJ. Biochemical investigations into the mode of action of trazodone. Neuropharmacology. 1980;**19**:1165-1173

[60] Cioli V, Corradino C, Piccinelli D, Rocchi MG, Valeri P. A comparative pharmacological study of trazodone, etoperidone and 1-(m-chlorophenyl) piperazine. Pharmacological Research Communications. 1984;**16**:85-100

[61] Nacca A, Guiso G, Fracasso C, Cervo L, Caccia S. Brain-to-blood partition and in vivo inhibition of 5-hydroxytryptamine reuptake and quipazine-mediated behaviour of nefazodone and its main active metabolites in rodents. British Journal of Pharmacology. 1998;**1998**:1617-1623

[62] Wettstein JG, Host M, Hitchcock JM. Selectivity of action of typical and atypical anti-psychotic drugs as antagonists of the behavioral effects of 1-[2,5-dimethoxy-4-iodophenyl]- 2-aminopropane (DOI). Progress in Neuro-Psychopharmacology & Biological Psychiatry. 1999;**23**:533-544

[63] Goodwin GM, Green AR, Johnson P. 5-HT2 receptor characteristics in frontal cortex and 5-HT2 receptormediated head-twitch behavior following antidepressant treatment to mice. British Journal of Pharmacology. 1984;**83**:235-242

[64] Godfrey PP, McClue SJ, Young MM, Heal DJ. 5-hydroxytryptaminestimulated inositol phospholipid hydrolysis in the mouse cortex has pharmacological characteristics compatible with mediation via 5-HT2 receptors but this response does not reflect altered 5-HT2 function after 5,7-dihydroxytryptamine lesioning or repeated antidepressant

treatments. Journal of Neurochemistry. 1988;**50**:730-738

[65] Pawlowski L, Ruczynska J, Gorka Z. Citalopram: A new potent inhibitor of serotonin (5-HT) uptake with central 5-HT-mimetic properties. Psychopharmacology. 1981;**74**:161-165

[66] Pawlowski L, Melzacka M. Inhibition of head twitch response to quipazine in rats by chronic amitriptyline but not fluvoxamine or citalopram. Psychopharmacology. 1986;**88**:279-284

[67] Kawakami Y, Kitamura Y, Araki H, Kitagawa K, Suemaru K, Shibata K, et al. Effects of monoamine reuptake inhibitors on wet-dog shakes mediated by 5-HT2A receptors in ACTH-treated rats. Pharmacology, Biochemistry, and Behavior. 2005;**81**:65-70

[68] Kitamura Y, Araki H, Suemaru K, Gomita Y. Effects of imipramine and lithium on wet-dog shakes mediated by the 5-HT2A receptor in ACTH-treated rats. Pharmacology, Biochemistry, and Behavior. 2002;**72**:397-402

[69] Marek GJ, Day M, Hudzik TJ. The utility of impulsive bias and altered decision making as predictors of drug efficacy and target selection: Rethinking behavioral screening for antidepressant drugs. The Journal of Pharmacology and Experimental Therapeutics. 2016;**356**:534-548

[70] O'Donnell JM, Marek GJ, Seiden LS. Antidepressant effects assessed using behavior maintained under a differential-reinforcement-of-low-rate (DRL) operant schedule. Neuroscience and Biobehavioral Reviews. 2005;**29**:785-798

[71] Marek GJ, Li AA, Seiden LS. Selective 5-hydroxytryptamine2 antagonists have antidepressant-like effects on

differential-reinforcement-of-lowrate 72-second schedule. The Journal of Pharmacology and Experimental Therapeutics. 1989;**250**(1):52-59

[72] Marek GJ, Martin-Ruiz R, Abo A, Artigas F. The selective 5-HT2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine. Neuropsychopharmacology. 2005;**30**:2205-2215

[73] Marek GJ, Seiden LS. Effects of selective 5-hydroxytryptamine-2 and nonselective 5-hydroxytryptamine antagonists on the differentialreinforcement-of-low-rate 72-second schedule. The Journal of Pharmacology and Experimental Therapeutics. 1988;**244**(2):650-658

[74] Ardayfio PA, Benvenga MJ, Chaney SF, Love PL, Catlow J, Swanson SP, et al. The 5-hydroxytryptamine2A receptor antagonist R-(+) a-(2,3-dimethoxyphenyl)- 1-[2-(4-fluorophenyl) ethyl-4-piperidinemethanol] (M100907) attenuates impulsivity after both drug-induced disruption (dizocilpine) and enhancement (antidepressant drugs) of differentialreinforcement-of-low-rate 72-s behavior in the rat. The Journal of Pharmacology and Experimental Therapeutics. 2008;**327**:891-897

[75] Fell MJ, Witkin JM, Falcone JF, Katner JS, Perry KW, Hart J, et al. N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl) benzyl)-1-methyl-1H-imidazole-4-carboxamide (THIIC), a novel metabotropic glutamate 2 potentiator with potential anxiolytic/antidepressant properties: In vivo profiling suggests a link between behavioral and central nervous system neurochemical changes. The Journal of Pharmacology and Experimental Therapeutics. 2011;**336**:165-177

[76] Nikiforuk A, Popik P, Drescher KU, van Gaalen M, Relo A-L, Mezler M, et al. Effects of a positive allosteric modulatory of group II metabotropic glutamate receptors, LY487379, on cognitive flexibility and impulsivelike responding in rats. The Journal of Pharmacology and Experimental Therapeutics. 2010;**335**:665-673

[77] Li AA, Marek GJ, Hand TH, Seiden LS. Antidepressant-like effects of trazodone on a behavioral screen are mediated by trazodone, not the metabolite m-chlorophenylpiperazine. European Journal of Pharmacology. 1990;**177**(3):137-144

[78] Gotter AL, Webber AL, Coleman PJ, Renger JJ, Windrow CJ. International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin receptor function, nomenclature and pharmacology. Pharmacological Reviews. 2012;**64**:389-420

[79] Kuriyama A, Tabata H. Suvorexant for the treatment of primary insomnia: A systematic review and meta-analysis. Sleep Medicine Reviews. 2017;**35**:1-7

[80] Black J, Pillar G, Hedner J, Polo O, Berkani O, Mangialaio S, et al. Efficacy and safety of almorexant in adult chronic insomnia: A randomized placebo-controlled trial with an active reference. Sleep Medicine. 2017;**36**:86-94

[81] Connor KM, Mahoney E, Jackson S, Hutzelmann J, Zhao X, Jia N, et al. A phase II dose-ranging study evaluating the efficacy and safety of the orexin receptor antagonist filorexant (MK-6096) in patients with primary insomnia. The International Journal of Neuropsychopharmacology. 2016;**19**(8):1-10

[82] Murphy P, Moline M, Mayleben D, Rosenberg R, Zammit G, Pinner K, et al. Lemborexant, a dual orexin receptor antagonist (DORA) for the

**101**

*Orexin 2 Receptor Antagonists from Prefrontal Cortical Circuitry to Rodent Behavioral Screens*

association cortex. Neuroscience.

Neuroscience. 2014;**8**(5):1-11

[91] Menezes MM, Santini MA, Benvenga MJ, Marek GJ, Merchant KM, Mikkelsen JD, et al. The mGlu2/3 receptor agonists LY354740 and LY379268 differentially regulate restraint-stress-induced expression of c-fos in rat cerebral cortex. Neuroscience Journal. 2013;**736439**:8

[92] Klodzinska A, Bijak M, Chojnacka-Wojcik E, Kroczka B, Swiader M, Czuczwar SJ, et al. Roles of group II metabotropic glutamate receptor agonists in modulation of seizure activity. Naunyn-Schmiedeberg's Archives of Pharmacology.

[93] Marek GJ. Activation of adenosine1 (A1) receptors suppresses head shakes induced by a serotonergic hallucinogen

in rats. Neuropharmacology.

[94] Recourt K, Van Amerongen G, Jacobs G, Zuiker R, Luthringer R, Van der Ark P, et al. JNJ-42847922/ MIN-202, a selective orexin 2 receptor antagonist, demonstrates beneficial effects on mood and sleep with major depressive disorder. European Neuropsychopharmacology.

[95] Connor KM, Ceesay P, Hutzelmann J, Snavely D, Krystal AD, Trivedi MH, et al. Phase II proof-of-concept trial of the orexin receptor antagonist filorexant (MK-6096) in patients with major depressive disorder. The International

2000;**361**:283-288

2009;**56**:1082-1087

2017;**27**(Suppl. 4):S866

[90] Fitch TE, Benvenga MJ, Jesudason CD, Zink C, Vandergriff AB, Menezes MM, et al. LSN2424100: A novel, potent orexin-2 receptor antagonist with selectivity over orexin-1 receptors and activity in an animal model predictive of antidepressant-like efficacy. Frontiers in

1991;**40**(2):399-412

*DOI: http://dx.doi.org/10.5772/intechopen.82544*

treatment of insomnia disorder: Results from a Bayesian, adaptive, randomized, double-blind, placebo-controlled study. Journal of Clinical Sleep Medicine.

[83] Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, et al. Differential expression of orexin receptors 1 and 2 in the rat brain. The Journal of Comparative Neurology.

2017;**13**:1289-1299

2001;**435**:6-25

[84] Lambe EK, Aghajanian GK. Hypocretin (orexin) induces calcium transients in single spines postsynaptic to identified thalamocortical boutons in prefrontal slice. Neuron. 2003;**40**:139-150

[85] Bayer L, Eggermann E, Saint-Mleux B, Machard D, Jones BE, Muhlethaler M, et al. Selective action of orexin (hypocretin) on nonspecific thalamocortical projection neurons. The Journal of Neuroscience.

[86] Lambe EK, Liu RJ, Aghajanian GKS. Hypocretin (orexin), and the thalamocortical activating system. Schizophrenia Bulletin.

2002;**22**:7835-7839

2007;**33**:1284-1290

1972;**176**:424-426

1995;**21**:42-92

[87] Gutnick MJ, Prince DA. Thalamocortical relay neurons: Antidromic invasion of spikes from a cortical epileptogenic focus. Science.

[88] Pinault D. Backpropogation of action potentials generated at ectopic axonal loci: Hypothesis that axon terminals integrate local environmental signals. Brain Research Reviews.

[89] Araneda R, Andrade R. 5-Hydroxytryptamine2 and 5-Hydroxytryptamine1A receptors mediate opposing responses on membrane excitability in rat

*Orexin 2 Receptor Antagonists from Prefrontal Cortical Circuitry to Rodent Behavioral Screens DOI: http://dx.doi.org/10.5772/intechopen.82544*

treatment of insomnia disorder: Results from a Bayesian, adaptive, randomized, double-blind, placebo-controlled study. Journal of Clinical Sleep Medicine. 2017;**13**:1289-1299

*Antidepressants - Preclinical, Clinical and Translational Aspects*

[76] Nikiforuk A, Popik P, Drescher KU, van Gaalen M, Relo A-L, Mezler M, et al. Effects of a positive allosteric modulatory of group II metabotropic glutamate receptors, LY487379, on cognitive flexibility and impulsivelike responding in rats. The Journal of Pharmacology and Experimental Therapeutics. 2010;**335**:665-673

[77] Li AA, Marek GJ, Hand TH, Seiden LS. Antidepressant-like effects of trazodone on a behavioral screen are mediated by trazodone, not the metabolite m-chlorophenylpiperazine. European Journal of Pharmacology.

[78] Gotter AL, Webber AL, Coleman PJ, Renger JJ, Windrow CJ. International

[79] Kuriyama A, Tabata H. Suvorexant for the treatment of primary insomnia: A systematic review and meta-analysis. Sleep Medicine Reviews. 2017;**35**:1-7

[80] Black J, Pillar G, Hedner J, Polo O, Berkani O, Mangialaio S, et al. Efficacy and safety of almorexant in adult chronic insomnia: A randomized placebo-controlled trial with an active reference. Sleep Medicine.

[81] Connor KM, Mahoney E, Jackson S, Hutzelmann J, Zhao X, Jia N, et al. A phase II dose-ranging study evaluating the efficacy and safety of the orexin receptor antagonist filorexant (MK-6096) in patients with primary insomnia. The International Journal of Neuropsychopharmacology.

[82] Murphy P, Moline M, Mayleben D, Rosenberg R, Zammit G, Pinner K, et al. Lemborexant, a dual orexin receptor antagonist (DORA) for the

1990;**177**(3):137-144

Union of Basic and Clinical Pharmacology. LXXXVI. Orexin receptor function, nomenclature and pharmacology. Pharmacological

Reviews. 2012;**64**:389-420

2017;**36**:86-94

2016;**19**(8):1-10

differential-reinforcement-of-lowrate 72-second schedule. The Journal of Pharmacology and Experimental Therapeutics. 1989;**250**(1):52-59

[72] Marek GJ, Martin-Ruiz R, Abo A, Artigas F. The selective 5-HT2A receptor antagonist M100907 enhances

[73] Marek GJ, Seiden LS. Effects of selective 5-hydroxytryptamine-2 and nonselective 5-hydroxytryptamine antagonists on the differentialreinforcement-of-low-rate 72-second schedule. The Journal of Pharmacology and Experimental Therapeutics.

[74] Ardayfio PA, Benvenga MJ, Chaney SF, Love PL, Catlow J, Swanson SP, et al. The 5-hydroxytryptamine2A

antidepressant-like behavioral effects of the SSRI fluoxetine. Neuropsychopharmacology.

2005;**30**:2205-2215

1988;**244**(2):650-658

receptor antagonist R-(+) a-(2,3-dimethoxyphenyl)- 1-[2-(4-fluorophenyl)

ethyl-4-piperidinemethanol] (M100907) attenuates impulsivity after both drug-induced disruption (dizocilpine) and enhancement (antidepressant drugs) of differentialreinforcement-of-low-rate 72-s behavior in the rat. The Journal of Pharmacology and Experimental Therapeutics.

[75] Fell MJ, Witkin JM, Falcone JF, Katner JS, Perry KW, Hart J, et al. N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl) benzyl)-1-methyl-1H-imidazole-4-carboxamide (THIIC), a novel metabotropic glutamate 2 potentiator with potential anxiolytic/antidepressant properties: In vivo profiling suggests a link between behavioral and central nervous system neurochemical

changes. The Journal of Pharmacology and Experimental Therapeutics.

2008;**327**:891-897

**100**

2011;**336**:165-177

[83] Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, et al. Differential expression of orexin receptors 1 and 2 in the rat brain. The Journal of Comparative Neurology. 2001;**435**:6-25

[84] Lambe EK, Aghajanian GK. Hypocretin (orexin) induces calcium transients in single spines postsynaptic to identified thalamocortical boutons in prefrontal slice. Neuron. 2003;**40**:139-150

[85] Bayer L, Eggermann E, Saint-Mleux B, Machard D, Jones BE, Muhlethaler M, et al. Selective action of orexin (hypocretin) on nonspecific thalamocortical projection neurons. The Journal of Neuroscience. 2002;**22**:7835-7839

[86] Lambe EK, Liu RJ, Aghajanian GKS. Hypocretin (orexin), and the thalamocortical activating system. Schizophrenia Bulletin. 2007;**33**:1284-1290

[87] Gutnick MJ, Prince DA. Thalamocortical relay neurons: Antidromic invasion of spikes from a cortical epileptogenic focus. Science. 1972;**176**:424-426

[88] Pinault D. Backpropogation of action potentials generated at ectopic axonal loci: Hypothesis that axon terminals integrate local environmental signals. Brain Research Reviews. 1995;**21**:42-92

[89] Araneda R, Andrade R. 5-Hydroxytryptamine2 and 5-Hydroxytryptamine1A receptors mediate opposing responses on membrane excitability in rat

association cortex. Neuroscience. 1991;**40**(2):399-412

[90] Fitch TE, Benvenga MJ, Jesudason CD, Zink C, Vandergriff AB, Menezes MM, et al. LSN2424100: A novel, potent orexin-2 receptor antagonist with selectivity over orexin-1 receptors and activity in an animal model predictive of antidepressant-like efficacy. Frontiers in Neuroscience. 2014;**8**(5):1-11

[91] Menezes MM, Santini MA, Benvenga MJ, Marek GJ, Merchant KM, Mikkelsen JD, et al. The mGlu2/3 receptor agonists LY354740 and LY379268 differentially regulate restraint-stress-induced expression of c-fos in rat cerebral cortex. Neuroscience Journal. 2013;**736439**:8

[92] Klodzinska A, Bijak M, Chojnacka-Wojcik E, Kroczka B, Swiader M, Czuczwar SJ, et al. Roles of group II metabotropic glutamate receptor agonists in modulation of seizure activity. Naunyn-Schmiedeberg's Archives of Pharmacology. 2000;**361**:283-288

[93] Marek GJ. Activation of adenosine1 (A1) receptors suppresses head shakes induced by a serotonergic hallucinogen in rats. Neuropharmacology. 2009;**56**:1082-1087

[94] Recourt K, Van Amerongen G, Jacobs G, Zuiker R, Luthringer R, Van der Ark P, et al. JNJ-42847922/ MIN-202, a selective orexin 2 receptor antagonist, demonstrates beneficial effects on mood and sleep with major depressive disorder. European Neuropsychopharmacology. 2017;**27**(Suppl. 4):S866

[95] Connor KM, Ceesay P, Hutzelmann J, Snavely D, Krystal AD, Trivedi MH, et al. Phase II proof-of-concept trial of the orexin receptor antagonist filorexant (MK-6096) in patients with major depressive disorder. The International

Journal of Neuropsychopharmacology. 2017;**20**:613-618

[96] Nollet M, Gaillard P, Tanti A, Girault V, Belzung C, Leman S. Neurogenesis-independent antidepressant-like effects on behavior and stress axis response of a dual orexin receptor antagonist in a rodent model of depression. Neuropsychopharmacology. 2012;**37**:2210-2221

[97] Scott MM, Marcus JN, Pettersen A, Birnbaum SG, Mochizuki T, Scammell TE, et al. Hcrtr1 and 2 signaling differentially regulates depression-like behaviors. Behavioural Brain Research. 2011;**222**:289-294

**103**

**Chapter 6**

The BDNF Loop 4

Dipeptide Mimetic Bis(*N*-

monosuccinyl-L-seryl-L-lysine)

in a Depression Model in Mice

*Polina Povarnina, Yulia N. Firsova, Anna V. Tallerova,* 

*Аrmen G. Mezhlumyan, Sergey V. Kruglov,* 

*Sergey B. Seredenin*

synaptogenesis, synaptophysin

**1. Introduction**

**Abstract**

*Tatiana A. Antipova, Tatiana A. Gudasheva and* 

**Keywords:** BDNF, depression, dipeptide mimetic GSB-106, anhedonia,

as one of the most pressing pharmacology problems.

after Acute Oral Administration

Low-molecular mimetic BDNF GSB-106, which is a substituted dimeric dipeptide, bis(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide, was designed and synthesized in the V. V. Zakusov Research Institute of Pharmacology. The dipeptide activates TrkB, PI3K/AKT, and MAPK/ ERK. GSB-106 is being developed as a potential antidepressant. Its antidepressant activity was detected in a number of rodent tests (0.1–1.0 mg/kg, ip; 0.5–5.0 mg/kg, po). In the present study, GSB-106 was shown to completely eliminate the manifestation of anhedonia in the sucrose preference test and to increase disturbed hippocampal synaptogenesis at acute oral administration (0.1 mg/kg) after 10-day social defeat stress in C57Bl/6 mice.

Depression is one of the most widespread mental disorders leading to social disadaptation. According to the WHO data in 2012, there were more than 350 million people suffering from depression. Modern antidepressants require long-term use to achieve a therapeutic effect, while their effectiveness does not exceed 60% [1]. Therefore, the creation of antidepressants with new action mechanisms is regarded

Fundamental studies established that the pathogenesis of depression was associated with impaired neuroplasticity in the hippocampus and the prefrontal cortex, caused by deficit of brain-derived neurotrophic factor (BDNF) [2]. The clinical

hexamethylenediamide Is Active

#### **Chapter 6**

*Antidepressants - Preclinical, Clinical and Translational Aspects*

Journal of Neuropsychopharmacology.

antidepressant-like effects on behavior and stress axis response of a dual orexin receptor antagonist in a rodent model of depression. Neuropsychopharmacology.

[97] Scott MM, Marcus JN, Pettersen A, Birnbaum SG, Mochizuki T, Scammell TE, et al. Hcrtr1 and 2 signaling differentially regulates depression-like behaviors. Behavioural Brain Research.

[96] Nollet M, Gaillard P, Tanti A, Girault V, Belzung C, Leman S. Neurogenesis-independent

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