**3.3. OXT and animal maternal behavior**

The importance of OXT in the establishment of maternal care was initially reported in the late 70's and early 80's through icv injections of OXT [46, 47], which have been supported by OXT antagonist administration [48-50]. OXT receptor knockout mice exhibit deficits in maternal care [51]. However, central OXT activity may not be a factor in all aspects of maternal care. The initiation of maternal care is impaired by the disruption of central OXT activity by lesions and antagonism of OXT [11], but since OXT disrupting lesions to the PVN of sheep do not disrupt maternal care once it has been established, OXT appears to be more important in the initiation of maternal care than the maintenance [52]. Other investigations in sheep have supported the hypothesis that OXT specifically mediates the induction of maternal care [53]. Comprehensive studies of natural variations in rodent maternal care indicate that OXT receptors mediate these differences, with high levels of OXT activity being associated with elevated levels of maternal care [54, 55]. These OXT actions are related to associated changes in dopamine activity [56] and both OXT receptor levels and maternal care are altered by exposure to gestational stress [57]. It is postulated that impairments in maternal care following gestational stress may be mediated by decreases in central OXT activity. The actions of OXT receptors in the nucleus accumbens have also been implicated in spontaneous maternal care in prairie voles [58]. OXT's role in maternal care induction parallels the importance of this peptide in parturition and lactation, and there is clinical interest in these parallels. Future animal work which includes the behavioral and physiological effects of OXT in maternal animals may identify treatments for disorders involving deficits in both maternal care and lactation.

#### **3.4. OXT in female animal models of depression and anxiety**

52 Neuroendocrinology and Behavior

**3. Oxytocin in female animals** 

**3.1. OXT and female animal affiliation** 

solicitation of sex and increased OXT levels [9].

**3.2. OXT and female animal aggression** 

OXT is inhibitory towards female aggression.

**3.3. OXT and animal maternal behavior** 

recognition is reversed by OXT treatment [7] and is mediated by the transmembrane protein CD38 [25]. A single dose of OXT can specifically impair memory retention [26], and further study indicates that exogenous OXT inhibits cholinergic mechanisms that are necessary for memory retention [27]. Another mechanism implicated in the amnesiac effects of OXT is glucocorticoid release, as dexamethasone is able to reverse the effects of OXT on memory [28]. While OXT may facilitate memory and social interactions in certain contexts such as pair bonds at certain levels, robust levels of OXT may impair social memory due to

OXT mediates the establishment and support of social bonds in several female mammalian species. Central injection of OXT specifically facilitates pair bonding in female prairie voles, similar to the role of AVP in males [3, 29, 30]. Studies of OXT receptor distributions in voles have identified expression patterns linked to species patterns of social organization, which support the manipulative studies [5, 11]. It has been postulated that the role of OXT in female rodent affiliation may be related to its effects on maternal behavior [31]. In primates, affiliation has been correlated with urinary OXT levels, including a relationship between the

The data on the role OXT in female aggression are mixed, including several studies specifically on maternal aggression [32]. Although it was initially concluded that OXT in the PVN had excitatory effects on maternal aggression [33, 34], more recent studies involving OXT manipulations in the CeA and BNST conclude that OXT has inhibitory effects on maternal aggression [35]. Other studies reporting a positive association between OXT and female aggression postulate that OXT increases aggression by attenuating fear [34, 36, 37], but it is also possible that elevated OXT levels following maternal aggression are a result of the stress of the encounter [36]. In contrast, maternal separation decreases OXT immunoreactivity in lactating female mice, and this decrease was associated with an decreased latency to attack a novel male intruder [38], supporting earlier studies reporting an inhibitory effect of OXT on maternal aggression [39-41]. Several studies of the effects of cocaine on maternal aggression and oxytocin have also concluded that oxytocin has inhibitory effects on aggression [42-44]. In multiparous rats which are more aggressive than primiparous dams, OXT or OXT receptor levels are decreased in several behaviorally relevant brain regions compared to primiparous animals [45]. In general, the majority of the manipulative studies support the conclusion that

The importance of OXT in the establishment of maternal care was initially reported in the late 70's and early 80's through icv injections of OXT [46, 47], which have been supported by

substantial glucocorticoid release or impaired cholinergic activity.

Despite the established role of OXT in maternal care, a potent reward mediated behavior; little effort has been directed at studying the role of OXT in female depression and anxiety. Much of the current focus on translational OXT work is centered on effects on social behavior, and related disorders such as seasonal affective disorder and autism. Central OXT decreases anxiety in pregnant and lactating rats, despite having no effect in virgins [59]. However, chronic icv OXT is anxiolytic in female rats selected for high levels of anxiety [21]. Studies using ovariectomized rats indicate that circulating estrogen is required for the anxiolytic effects of OXT, which is likely to involve dynamic estrogen dependent changes in OXT receptor levels [60]. This dependence on estrogen may explain the divergent results in maternal and nulliparous rats considering the robust hormonal changes of pregnancy and lactation [61]. Elevated plus maze (EPM) testing indicates that the anxiolytic effects of OXT may be most potent in stressful context, as OXT is only anxiolytic when the EPM is presented as a novel environment [62]. These data are relevant to the clinical observation that exposure to stress is a significant predictor of depression in females [63]. The animal literature on OXT and maternal care and the consistency between animal and human work make this neuropeptide a strong target for human studies of postpartum depression.

#### **3.5. OXT and female animal learning and memory**

The majority of the studies on OXT and memory in female animals investigate social recognition. The disruption of endogenous OXT activity impairs short-term olfactory memory in female rats [64], and mice with a conditional OXT knockout display impairments in social recognition [65]. In sheep, a functioning OXT circuit in the olfactory bulb is required for offspring recognition [52]. These effects of OXT on offspring recognition are mediated by GABA, norepinephrine, and acetylcholine and are crucial to the role of OXT in maternal care induction [66]. It has also been postulated that the effects of OXT in pair bonding involve a social recognition function [67]. Similar to studies of the roles of dopamine and AVP in rodent maternal memory (the ability of a dam to quickly return to maternal care following a separation from her pups) [68, 69], central OXT is involved in the consolidation of maternal memory [70]. One hypothesis is that the effects of both OXT and AVP are mediated by their actions on dopamine. Although some studies of ongoing maternal care conclude that OXT is not necessary once offspring care has been established [11, 52, 71], these data on maternal memory indicate that its importance to maternal care may extend beyond the initial stages of maternal care.

Behavioral Roles of Oxytocin and Vasopressin 55

**4.3. OXT and human paternal behavior** 

**4.4. OXT and male human depression and anxiety** 

associated social behavior.

for treating depression and/or anxiety.

amygdala [98].

**4.5. OXT and male human learning and memory** 

There is some evidence that OXT mediates human paternal care as well as maternal care. Plasma and salivary OXT has been associated with paternal social engagement, affect synchrony, and positive communication sequences, and fathers who exhibit high levels of stimulatory contact with 4-6 month old infants have elevated OXT levels compared to fathers that do not exhibit high levels of contact [86]. Intranasal OXT increases the responsiveness of fathers during play with their children, and may decrease hostility, which supports a causal role for OXT and positive paternal behavior [87]. The decrease in hostility offers indirect support for an inhibitory effect on male aggression. Finally, both maternal and paternal plasma OXT levels predict coordination of behaviors between parents and their children, indicating that OXT may have a positive effect on family interactions [88, 89]. Collectively, these recent studies indicate that OXT modulates several forms of family

The interest in OXT as a potential treatment for mood disorders is based on the animal literature supporting the involvement of OXT in reward mediated and social behaviors [90, 91], which are often impaired in depressed individuals. Reduced plasma OXT has been observed in humans suffering from depression [92, 93], and detailed investigations of depressive symptoms indicate that high levels of plasma OXT are associated with a decrease in the severity of symptoms [94]. However, some studies have been unable to find depression related differences in plasma OXT [95]. Since OXT has both central behavioral effects and peripheral physiological effects, the exact functions of elevated plasma OXT are not clear. The few studies which have measured OXT activity in postmortem samples of depressed patients have reported increases in depression associated OXT immunoreactivity [96] and OXT mRNA in the PVN [97]. The increase in OXT mRNA in melancholic patients compared to non-melancholic depressives suggests that changes in OXT are specific to the type of depression. With anxiety, intranasal OXT has minor effects in male patients with seasonal affective disorder [85]. Given the strength of the animal work on the prosocial and reward mediated actions of OXT, it is surprising that there is not more interest in this target

Intranasal OXT facilitates socially reinforced learning and emotional empathy in men [98], consistent with the data from animal models and the initial studies of the effects of OXT in autistic patients. Another study reported that OXT's effects were specific to the social stimuli of facial expressions, and did not affect financial associations in an associative learning task [99]. The available evidence supports the conclusion that OXT facilitates social reinforced learning and memory in human males, and these effects may be mediated at the
