**1. Introduction**

Orexin, also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, in which the sufferer experiences brief losses of muscle tone (cataplexy), is caused by a lack of orexin in the brain due to destruction of the cells that produce it. There are only 10,000–20,000 orexin-producing neurons in the human brain, located predominantly in the perifornical area and lateral hypothalamus. They project widely throughout the central nervous system, regulating wakefulness, feeding, and other behaviors. The orexin system was initially suggested to be primarily involved in the stimulation of food intake, based on the finding that central administration of orexin-A and orexin-B increased food intake. In addition, it stimulates wakefulness, regulates energy expenditure, and modulates visceral function [1, 2].

Two distinct types of orexin, orexin-A and orexin-B, were identified; they act on specific receptors called orexin receptor type 1 (OX1R) and orexin receptor type 2 (OX2R). Orexin-A activates both of these receptors equally, while orexin-B has a five times higher affinity to OX2R than OX1R. Upon activation, prepro-orexin will split to orexin-A and orexin-B, which act on their G protein-coupled receptors (**Figure 1**) [3].

Orexin receptors are distributed mainly in the lateral hypothalamus and adjacent areas, and their nerve fibers project to multiple brain regions. Orexinergic neurons in the lateral hypothalamus group are closely associated with reward-related functions. These neurons preferentially innervate the ventral tegmental area and the ventromedial prefrontal cortex. In contrast, the perifornical-dorsal group of orexinergic neurons is involved in functions related to arousal and autonomic response. These neurons project inter-hypothalamically, as well as to the brainstem, where the release of orexin modulates various autonomic processes**.** Indeed, accumulating evidence shows that the orexin/receptor system is ectopically expressed in several neurological disorders, suggesting that it plays an important role in the incidence and pathogenesis of these diseases [4].

It has been verified that hypothalamic orexigenic neurons are involved in reward functions, while prefrontal orexigenic neurons are linked in the regulation of autonomic and arousal functions. Moreover, orexin provokes and stimulates food intake via inhibition of autonomic digestive feedbacks. Orexigenic neurons are inhibited by leptin and food intake, while hypoglycemia and ghrelin activate orexigenic neurons. Amino acid and high-protein diets paradoxically provoke the hyperpolarization of orexigenic neurons and block glucose-induced orexigenic neuron activations [5]. Animal model studies have shown that orexin is a very important link between sleep and body metabolism since sleep deprivation leads to higher food intake and induction of catabolism [6].

Additionally, orexin stimulates different neurotransmitters which are linked to the activation of the central nervous system, including acetylcholine, histamine, noradrenaline, and dopamine. Therefore, mutations of orexin receptors lead to sleep disorders. Mice with orexin knockout are subjected to narcolepsy and excessive daytime sleepiness [7]. Alizamini et al. study showed that central

**47**

illustrated in **Figure 2**.

*Central and peripheral effects of orexin.*

**Figure 2.**

a systemic review.

**2. Method and search strategy**

*Orexin and Psychoneurobiology: A Hidden Treasure DOI: http://dx.doi.org/10.5772/intechopen.91852*

administration of orexin leads to stimulation of locomotion, psychomotor performance, body temperature, and energy expenditure. Furthermore, mice with orexin deficiency are subjected to obesity due to reduction of basal metabolic and energy expenditure rates. Beside, orexin knockout out mice is characterized by a reduction in brown adipose tissue thermogenesis with poor differentiation of pre-adipocyte into adipocytes in the adipose tissue [8]. Central and peripheral effects of orexin are

The aim of this study was to provide a narrative review of the neurobiological effect of orexin system and to examine the association between orexin neurotransmission and different psychoneurological disorders, including depression, schizophrenia, addiction, Parkinson's disease, and dementia. Evidence from experimental, preclinical and clinical studies is evaluated for bidirectional relationships between orexin neurobiology and psychoneurological disorders. Given the nature of the subject area, it remains clear that this literature search cannot be regarded as

A diversity of search strategies was adopted and assumed which included electronic database searches of Medline and PubMed using MeSH terms, keywords, and title words. There is no limitation for publication year. The terms used for these searches were as follows: [orexin OR hypocretin] AND [cognitive function OR vigilance OR depression OR schizophrenia OR addiction OR Alzheimer dementia OR stroke OR sleep disorders]. [suvorexant OR orexin antagonists] AND [sleep disorders OR vigilance OR depression OR schizophrenia OR addiction]. Reference lists of identified and notorious articles were reviewed. Besides, only English articles were considered, and case reports were not involved in the review. The key

*Orexin and Psychoneurobiology: A Hidden Treasure DOI: http://dx.doi.org/10.5772/intechopen.91852*

*Weight Management*

(**Figure 1**) [3].

and pathogenesis of these diseases [4].

induction of catabolism [6].

Two distinct types of orexin, orexin-A and orexin-B, were identified; they act on specific receptors called orexin receptor type 1 (OX1R) and orexin receptor type 2 (OX2R). Orexin-A activates both of these receptors equally, while orexin-B has a five times higher affinity to OX2R than OX1R. Upon activation, prepro-orexin will split to orexin-A and orexin-B, which act on their G protein-coupled receptors

Orexin receptors are distributed mainly in the lateral hypothalamus and adjacent areas, and their nerve fibers project to multiple brain regions. Orexinergic neurons in the lateral hypothalamus group are closely associated with reward-related functions. These neurons preferentially innervate the ventral tegmental area and the ventromedial prefrontal cortex. In contrast, the perifornical-dorsal group of orexinergic neurons is involved in functions related to arousal and autonomic response. These neurons project inter-hypothalamically, as well as to the brainstem, where the release of orexin modulates various autonomic processes**.** Indeed, accumulating evidence shows that the orexin/receptor system is ectopically expressed in several neurological disorders, suggesting that it plays an important role in the incidence

It has been verified that hypothalamic orexigenic neurons are involved in reward functions, while prefrontal orexigenic neurons are linked in the regulation of autonomic and arousal functions. Moreover, orexin provokes and stimulates food intake via inhibition of autonomic digestive feedbacks. Orexigenic neurons are inhibited by leptin and food intake, while hypoglycemia and ghrelin activate orexigenic neurons. Amino acid and high-protein diets paradoxically provoke the hyperpolarization of orexigenic neurons and block glucose-induced orexigenic neuron activations [5]. Animal model studies have shown that orexin is a very important link between sleep and body metabolism since sleep deprivation leads to higher food intake and

Additionally, orexin stimulates different neurotransmitters which are linked to the activation of the central nervous system, including acetylcholine, histamine, noradrenaline, and dopamine. Therefore, mutations of orexin receptors lead to sleep disorders. Mice with orexin knockout are subjected to narcolepsy and excessive daytime sleepiness [7]. Alizamini et al. study showed that central

**46**

**Figure 1.**

*Schematic representation of orexin system.*

**Figure 2.** *Central and peripheral effects of orexin.*

administration of orexin leads to stimulation of locomotion, psychomotor performance, body temperature, and energy expenditure. Furthermore, mice with orexin deficiency are subjected to obesity due to reduction of basal metabolic and energy expenditure rates. Beside, orexin knockout out mice is characterized by a reduction in brown adipose tissue thermogenesis with poor differentiation of pre-adipocyte into adipocytes in the adipose tissue [8]. Central and peripheral effects of orexin are illustrated in **Figure 2**.

The aim of this study was to provide a narrative review of the neurobiological effect of orexin system and to examine the association between orexin neurotransmission and different psychoneurological disorders, including depression, schizophrenia, addiction, Parkinson's disease, and dementia. Evidence from experimental, preclinical and clinical studies is evaluated for bidirectional relationships between orexin neurobiology and psychoneurological disorders. Given the nature of the subject area, it remains clear that this literature search cannot be regarded as a systemic review.

#### **2. Method and search strategy**

A diversity of search strategies was adopted and assumed which included electronic database searches of Medline and PubMed using MeSH terms, keywords, and title words. There is no limitation for publication year. The terms used for these searches were as follows: [orexin OR hypocretin] AND [cognitive function OR vigilance OR depression OR schizophrenia OR addiction OR Alzheimer dementia OR stroke OR sleep disorders]. [suvorexant OR orexin antagonists] AND [sleep disorders OR vigilance OR depression OR schizophrenia OR addiction]. Reference lists of identified and notorious articles were reviewed. Besides, only English articles were considered, and case reports were not involved in the review. The key

features of recognized relevant search studies were considered, and the conclusions were summarized in a narrative review.

#### **2.1 Orexin and cognitive function**

Orexin regulates behavioral and neuroendocrine response during stressful conditions as these events lead to the impairment of cognitive flexibility and function. Also, patients with psychiatric disorders such as panic disorder are associated with significant reduction of hypothalamic orexin activations [9].

It has been shown that stress improves male cognitive flexibility, but it worsens female cognitive flexibility due to gender differences in stress-induced orexin neuropeptide activations. Women are twice as likely as men to suffer from stress-related psychiatric disorders, such as post-traumatic stress disorder (PTSD) and major depressive disorder (MDD); however, the biological basis of these sex differences is not fully understood. Interestingly, orexins are known to be dysregulated in these disorders. Both preclinical and clinical studies have reported higher orexin system expression in females, which contributes to exaggerated neuroendocrine and behavioral responses to stress. Therefore, orexins may be important in the etiology of stress-related psychiatric disorders that present differently in men and women [10]. Piantadosi et al. illustrated that stimulation of prefrontal cholinergic neurons leads to the release of orexin from hypothalamic neurons, which play an important role in cognitive activation since high orexin activates the arousal state and executive functions via activation of cortical cholinergic neurons [11]. Chieffi et al. study reported the beneficial effects of exercise in stimulation of orexin release due to enhancement of hippocampal activity as exercise attenuates hippocampal deterioration and depressive symptoms in elderly persons through regulation of orexin release [12].

Notably, cognitive impairment is the main feature of neurological and neuropsychiatric disorders as in dementia and narcolepsy, which are linked to orexin dysfunction. Therefore, intranasal orexin peptide may be an effective agent for cognitive dysfunction [13]. Astonishingly, orexin plays a crucial role in activation of learning and memory, as orexin-A provokes memory acquisition and consolidation through activation of monoaminergic system. Consequently, orexin antagonist leads to significant memory dysfunction in the experimental rats [14]. Kim et al. study revealed that orexin is an important key factor of hippocampal neurogenesis as orexin-A participates in the hippocampal neuronal proliferation and neuroprotection following stroke; thus orexin agonist participates in prevention of negative stroke outcomes [15]. On the other hand, Uslaner et al. exhibited that dual orexin receptor antagonists (DORA-22) is an effective sedative agent, with less cognitive disability than GABA allosteric modulators, which cause significant cognitive dysfunctions [16, 17]. Therefore, orexin improves cognitive functions as illustrated in different human and animal studies (**Table 1**).

#### **2.2 Orexin and neuroendocrinology**

Orexin is involved in the regulation of central and peripheral signals to regulate metabolic homeostasis. Alongside, orexin stimulates adrenocorticotrophin (ACTH) and corticosteroid secretions via activation of central corticotropin-releasing hormone (CRH) and vasopressin. Therefore, orexin through OX2R receptor controls the hypothalamic-pituitary-adrenal axis (HPA) [18]. Previously, Malendowicz et al. illustrated that chronic orexin administration led to dose-dependent increase in cortisol and aldosterone plasma levels independent of ACTH levels, indicating a

**49**

*Orexin and Psychoneurobiology: A Hidden Treasure DOI: http://dx.doi.org/10.5772/intechopen.91852*

cholinergic neurons

Orexin-A administration

Mice Orexin-A administration Stimulates angiogenesis and

Animals Stimulation of prefrontal

Exercise

administration

receptor antagonists

Humans Intranasal orexin-A

Humans Administration of orexin

nervous system [20].

*Orexin and cognitive functions.*

Humans and animals

**Table 1.**

plasma levels [21, 22].

operating system [26].

*2.3.1 Orexin and depression*

tion of pancreatic islets life span [25].

**2.3 Orexin and psychiatric disorders**

direct stimulating effect of orexin on the adrenal cortex [19]. But in spite of these findings, Patel et al. study confirmed insignificant effect of orexin antagonists on ACTH and cortisol serum levels as well as on the markers of the sympathetic

**Species Interventions Results References**

↑ orexin

and consolidation

neuroprotection

neuroprotection

Provokes memory acquisition

Stimulates angiogenesis and

↑ orexin Piantadosi et al.

Improve cognition Calva and Fadel

[11]

[13]

Chieffi et al. [12]

Kim et al. [15]

Uslaner et al. [16]

It has been reported that orexin administration leads to significant suppression of the hypothalamic prolactin release, which is not upturned by dopamine receptor antagonists like metoclopramide suggesting a novel pathway in controlling of prolactin secretion. The mechanism of prolactin inhibition may be through inhibition of prolactin-releasing factor or stimulation of prolactin-inhibiting factor. But previous study illustrated insignificant effect of orexin antagonist on prolactin

Many studies showed that the blood glucose is regulated by central orexin through regulation of hepatic glucose production, skeletal glucose consumption and thermogenesis. High orexin or dysrhythmic in orexin secretion is linked with the development of obesity and insulin resistance [23, 24]. Thus, suvorexant and other orexin antagonists are effective in the management of obesity and insulin resistance via amelioration of body adiposity and augmentation of energy expenditure that improve glucose metabolism. Moreover, orexin-A has important roles in the regulation of pancreatic islet biology through activation of insulin secretion and prolonga-

Tsuneki et al. study illustrated that suvorexant improves glucose tolerance through inhibition of hepatic gluconeogenic factors, when administrated at resting time. However, administration of suvorexant at awaking time illustrates insignificant effect on glucose tolerance due to differential effects on the orexin sleep/wake

In addition, Flores et al. study illustrated an interaction between endocannabinoid and orexigenic neurons as there is a similarity between OX1R and CB1 receptors with diffuse overlapping in the anatomical distribution of these neurons. Therefore, the pharmacological effect of cannabinoid may be through orexigenic receptors [27]. The neuroendocrine effects of orexin are summarized in **Table 2**.

Among important etiological factors involved in the pathophysiology of depression, disturbances of monoamines and HPA are the main mechanistic pathways


#### **Table 1.**

*Weight Management*

release [12].

were summarized in a narrative review.

**2.1 Orexin and cognitive function**

features of recognized relevant search studies were considered, and the conclusions

Orexin regulates behavioral and neuroendocrine response during stressful conditions as these events lead to the impairment of cognitive flexibility and function. Also, patients with psychiatric disorders such as panic disorder are associated with

It has been shown that stress improves male cognitive flexibility, but it worsens female cognitive flexibility due to gender differences in stress-induced orexin neuropeptide activations. Women are twice as likely as men to suffer from stress-related psychiatric disorders, such as post-traumatic stress disorder (PTSD) and major depressive disorder (MDD); however, the biological basis of these sex differences is not fully understood. Interestingly, orexins are known to be dysregulated in these disorders. Both preclinical and clinical studies have reported higher orexin system expression in females, which contributes to exaggerated neuroendocrine and behavioral responses to stress. Therefore, orexins may be important in the etiology of stress-related psychiatric disorders that present differently in men and women [10]. Piantadosi et al. illustrated that stimulation of prefrontal cholinergic neurons leads to the release of orexin from hypothalamic neurons, which play an important role in cognitive activation since high orexin activates the arousal state and executive functions via activation of cortical cholinergic neurons [11]. Chieffi et al. study reported the beneficial effects of exercise in stimulation of orexin release due to enhancement of hippocampal activity as exercise attenuates hippocampal deterioration and depressive symptoms in elderly persons through regulation of orexin

Notably, cognitive impairment is the main feature of neurological and neuropsychiatric disorders as in dementia and narcolepsy, which are linked to orexin dysfunction. Therefore, intranasal orexin peptide may be an effective agent for cognitive dysfunction [13]. Astonishingly, orexin plays a crucial role in activation of learning and memory, as orexin-A provokes memory acquisition and consolidation through activation of monoaminergic system. Consequently, orexin antagonist leads to significant memory dysfunction in the experimental rats [14]. Kim et al. study revealed that orexin is an important key factor of hippocampal neurogenesis as orexin-A participates in the hippocampal neuronal proliferation and neuroprotection following stroke; thus orexin agonist participates in prevention of negative stroke outcomes [15]. On the other hand, Uslaner et al. exhibited that dual orexin receptor antagonists (DORA-22) is an effective sedative agent, with less cognitive disability than GABA allosteric modulators, which cause significant cognitive dysfunctions [16, 17]. Therefore, orexin improves cognitive functions as illustrated

Orexin is involved in the regulation of central and peripheral signals to regulate metabolic homeostasis. Alongside, orexin stimulates adrenocorticotrophin (ACTH) and corticosteroid secretions via activation of central corticotropin-releasing hormone (CRH) and vasopressin. Therefore, orexin through OX2R receptor controls the hypothalamic-pituitary-adrenal axis (HPA) [18]. Previously, Malendowicz et al. illustrated that chronic orexin administration led to dose-dependent increase in cortisol and aldosterone plasma levels independent of ACTH levels, indicating a

significant reduction of hypothalamic orexin activations [9].

in different human and animal studies (**Table 1**).

**2.2 Orexin and neuroendocrinology**

**48**

*Orexin and cognitive functions.*

direct stimulating effect of orexin on the adrenal cortex [19]. But in spite of these findings, Patel et al. study confirmed insignificant effect of orexin antagonists on ACTH and cortisol serum levels as well as on the markers of the sympathetic nervous system [20].

It has been reported that orexin administration leads to significant suppression of the hypothalamic prolactin release, which is not upturned by dopamine receptor antagonists like metoclopramide suggesting a novel pathway in controlling of prolactin secretion. The mechanism of prolactin inhibition may be through inhibition of prolactin-releasing factor or stimulation of prolactin-inhibiting factor. But previous study illustrated insignificant effect of orexin antagonist on prolactin plasma levels [21, 22].

Many studies showed that the blood glucose is regulated by central orexin through regulation of hepatic glucose production, skeletal glucose consumption and thermogenesis. High orexin or dysrhythmic in orexin secretion is linked with the development of obesity and insulin resistance [23, 24]. Thus, suvorexant and other orexin antagonists are effective in the management of obesity and insulin resistance via amelioration of body adiposity and augmentation of energy expenditure that improve glucose metabolism. Moreover, orexin-A has important roles in the regulation of pancreatic islet biology through activation of insulin secretion and prolongation of pancreatic islets life span [25].

Tsuneki et al. study illustrated that suvorexant improves glucose tolerance through inhibition of hepatic gluconeogenic factors, when administrated at resting time. However, administration of suvorexant at awaking time illustrates insignificant effect on glucose tolerance due to differential effects on the orexin sleep/wake operating system [26].

In addition, Flores et al. study illustrated an interaction between endocannabinoid and orexigenic neurons as there is a similarity between OX1R and CB1 receptors with diffuse overlapping in the anatomical distribution of these neurons. Therefore, the pharmacological effect of cannabinoid may be through orexigenic receptors [27]. The neuroendocrine effects of orexin are summarized in **Table 2**.

#### **2.3 Orexin and psychiatric disorders**

#### *2.3.1 Orexin and depression*

Among important etiological factors involved in the pathophysiology of depression, disturbances of monoamines and HPA are the main mechanistic pathways


#### **Table 2.**

*Neuroendocrine effects of orexin.*

leading to functional disorders of neuroplasticity, which is regarded as a cardinal step in the onset of depression [28].

Diurnal variation in orexin serum levels revealed that high orexin levels are occurring at the middle of night. It has been reported that orexin level is significantly decreased in patients with depression in comparison with healthy subjects [29]. But paradoxical high orexin serum levels are seen in some depressed patients, which is normalized by selective serotonin reuptake inhibitors. Since, orexin-A CSF levels are negatively correlated with depressive symptoms [30].

Long-term antidepressant agents improve orexin serum levels regardless of the type of antidepressant medications [31]. Nevertheless, there are different findings concerning orexin levels in depression. Feng et al. reported that depression is linked to reduction of serotonergic neuronal activity which is responsible for modulation of orexinergic activity [32]. Thus reduction of serotonergic neuronal activity leads to activation of orexin neuroactivity leading to depression. However, orexin levels are significantly reduced in depression compared with healthy control [33].

The initial animal model study observed reduction in the orexinergic neurons by 18% with diminution in size of these neurons in comparison with normal rats. As well, prepro-orexin mRNA expression and orexin-A were reduced compared with control [34].

Previous preclinical study revealed a strong connection between low orexin and risk of depression which are inconsistent with previous studies that illustrated hypoactivity of orexinergic neurons in patients with depression since short-term antidepressant therapy improves sleep pattern through increasing and decreasing the expression of mRNA of orexin-A and orexin-B, respectively [35].

Ito et al. showed that administration of orexin-A leads to significant reduction of despair behavior in depression with important hippocampal neurogenesis via upregulation of neuropeptide Y (NPY). These changes are inhibited by co-administration of orexin-A antagonist [36].

Therefore, orexin levels are different according to the pathophysiology of depression. Low orexin in depressed patients is associated with hypersomnia, whereas high orexin in depressed patients is associated with insomnia and interrupted sleep [17]. Ji et al. illustrated that orexinergic neurons have direct connection to the ventral pallidum (VP) which is concerned with stress response and rewarding system. Orexin stimulates the VP and prevents depressive behavior. Therefore, high orexin in the VP is associated with elevated serum corticosterone serum levels

**51**

**Figure 3.**

*Chemical structure of modafinil.*

*Orexin and Psychoneurobiology: A Hidden Treasure DOI: http://dx.doi.org/10.5772/intechopen.91852*

*2.3.2 Orexin and schizophrenia*

of orexinergic neurons [42].

induced sedation.

*2.3.3 Orexin and addiction*

events through improvement of stress resilience [37].

during acute stress, which per se prevent a depressive reaction against stressful

The association between orexin and schizophrenia had not been previously explored precisely [38]. Clinical and preclinical findings proposed that orexin and orexin agonist are of great value and useful in treating cognitive deficit in schizophrenia [39]. There are widespread connection and interaction between orexin and dopaminergic neurons in midbrain, thalamocortical region, and amygdala suggest-

Modafinil is an atypical dopamine reuptake inhibitor used in the treatment of narcolepsy and antipsychotic drug-induced sleep disorder (**Figure 3**) [41]. Modafinil has been revealed as a complement of drugs in therapy of schizophrenia, and it reduce negative symptoms with no effect on the positive symptoms. Modafinil improves locomotor and psychomotor performances through activation

Therefore, activations of orexinergic neurons by modafinil may be an imperative step for future antipsychotic medications. These findings document that dopaminergic agonists mainly at D1 and D2 receptors modify orexinergic neurotransmissions [43]. Also, dopamine antagonists that cause weight gain lead to activation of orexin pathway, but dopamine antagonists which do not cause weight gain do not activate orexin pathway [44]. Nevertheless, amphetamine which indirectly activates dopamine leads to activation of orexinergic neurotransmission despite induction of weight loss. Moreover, clozapine activates only orexinergic neurons in the prefrontal cortex [45]. Similarly, orexin antagonists abolish olanzapine and haloperidol effect on midbrain dopaminergic neurons, suggesting that orexin is an important neurotransmitter mediates the action of antipsychotic drugs [46]. As well, Chen et al. illustrated that orexin-A is stimulated and upregulated by non-obesegenic antipsychotic drugs [47]. Also, the high orexin level in patients with schizophrenia treated with antipsychotic drugs is regarded as a protective factor against the development and risk of drug-induced metabolic syndrome [48]. Furthermore, orexin agonist like modafinil ameliorates cognitive function, attention, and antipsychotic-

The orexinergic system has broad projections and connections to different brain area which are concerned with drug-induced neuro-adaptation, including midbrain dopaminergic neurons, ventral tegmental area (VTA), nucleus accumbens (NA),

ing the potential role of orexinergic neurons in schizophrenia [40].

during acute stress, which per se prevent a depressive reaction against stressful events through improvement of stress resilience [37].
