**2.4. OXT and male animal models of depression and anxiety**

Peripheral OXT has antidepressant effects in both young and old rats, and the effects in older rats are associated with enhanced memory [18, 19]. In the mouse tail suspension test, both systemic and central OXT decrease immobility time, which indicates that OXT decreased helplessness [20]. In contrast to these results, intracerebroventricular (icv) OXT did not affect behavior in the forced swim test of depressive like behavior in male rats selected for high or low anxiety, although it did have an anxiolytic effect [21]. Furthermore, isolated prairie vole males exhibit both anhedonia and increased plasma OXT following a resident intruder test of aggression [22]. As has been hypothesized for OXT elevation following maternal aggression, this increase could be due to the stress of the interaction, and may not be a causal factor for anhedonia. It is possible that anhedonia targeting tests of depressive behavior, such as saccharin preference or a naturally occurring reward mediated behavior (sexual behavior, maternal behavior), would reveal consistent anti-depressive actions of OXT.

#### **2.5. OXT and male animal learning and memory**

Most of the research on OXT and learning and memory has been limited to male models [23]. OXT mediates social recognition in several species [24], and male OXT knockout mice exhibit social amnesia [6], while other forms of memory are not affected. This effect on social

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 substantial glucocorticoid release or impaired cholinergic activity.

Behavioral Roles of Oxytocin and Vasopressin 53

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.

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

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

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.

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
