**6.4. AVP and male animal models of depression and anxiety**

58 Neuroendocrinology and Behavior

**6. AVP in male animals** 

**6.1. AVP and male animal affiliation** 

**6.2. AVP and male animal aggression** 

There is a wealth of studies of AVP and affiliation in voles [11]. Central administration of AVP to monogamous prairie voles that live in burrows with extended families induces several forms of bonding behaviors [124, 125], and AVP V1a receptor antagonist treatment blocks pair bonding behaviors in males [124, 125]. In polygamous montane voles (*Microtus montanus*) that live in solitary burrows, AVP or V1a antagonist treatments have no effects on social behavior. These behavioral differences are reflected in the neural OXT and AVP maps of these species [5]. Over-expression of V1a receptors in the forebrain of male prairie voles enhances pair bonding [126], and V1a antagonist injection into specific brain regions inhibit pair bond formation [127, 128]. The pattern of AVP mediated pair bonding in males and OXT mediated pair bonding in females has been identified in several other species [129]. Although there is no clear picture of how AVP expression patterns relate to social structure, AVP is an important mediator of affiliation in many vertebrate species, including fish [2] and birds [1]. The variety of social structures and central AVP circuitry among vertebrate species presents a valuable

Initial studies in male hamsters reported that V1a antagonist administration into the anterior hypothalamus inhibits aggression [130, 131], results which have since been confirmed in several other labs [132-134]. Exogenous AVP in the anterior hypothalamus can stimulate offensive aggression [133, 135], but this effect may be modulated by social environment [136]. Further work in hamsters has revealed that an orally active V1a antagonist decreases aggression in male hamsters, but does not affect social investigation or sexual motivation [137]. Anabolic steroid treatment of adolescent males increases aggression which can be inhibited by V1a antagonist treatment in the AH [138], indicating that the elevated aggression is mediated by central AVP activity. A similar effect of amphetamine has been documented in male prairie voles, where increased aggression is associated with increased V1a receptor binding in the AH [134]. Developmental effects of AVP have been reported in male prairie voles, where early postnatal peripheral injections of AVP increase adult aggression [139]. However, maternal separation in mice increases AVP in the paraventricular nucleus and decreases intermale aggression [38]. This effect is similar to much of the behavioral data from female animals, which indicate that AVP has suppressive

Research on AVP and offspring care by males includes studies in several rodent species. The increase in paternal behavior in cohabitating meadow voles is mediated by AVP, as treatment with AVP antagonist decreases paternal behavior [14, 140]. Elevated AVP in meadow voles stimulates paternal behavior through both a decrease in pup directed

opportunity for both descriptive and manipulative comparative studies.

effects on maternal aggression and intraspecies aggression.

**6.3. AVP and animal paternal behavior** 

Anxiety related behavior on the elevated plus maze is decreased following septal AVP antagonist treatment or antisense treatment in male rats [143, 144]. In contrast, other studies report that intraseptal and intraperitoneal AVP is anxiolytic [145]. An anxiogenic role of AVP is supported by male AVP V1a receptor knockout mice which exhibit lower levels of anxiety compared to wild type [24, 146]. Once again, other investigations of this line have failed to find differences in anxiety [147]. The oral and intraperitoneal administration of an AVP V1b antagonist is anxiolytic in several tests of anxiety [148-150], but AVP V1b receptor knockout males may not exhibit decreased anxiety [147, 151]. The lack of differences in anxiety related behaviors in these knockout mice may be due to compensatory mechanisms during development. In male rats bred for high levels of anxiety, AVP level and release from the PVN are elevated when compared to low anxiety males [152-154] and the differential expression of AVP in rats selected for high anxiety has been linked to specific single nucleotide polymorphisms [155, 156]. Central AVP V1a receptor antagonist treatment decreases anxiety and depression associated behaviors in high anxiety males [154]. The forced swim test induces both depression associated behavior and elevated AVP in the SON and PVN [157, 158]. V1a antagonist treatment to both the mediolateral septum and amygdala has antidepressant like effects in male animals [159, 160], and similar effects are documented following V1b receptor antagonist treatment [148, 161]. For male animals, there is evidence to support the hypothesis that depression and anxiety related behaviors are associated with elevated AVP activity in both brain and plasma.

## **6.5. AVP and male animal learning and memory**

Infusion of AVP into the lateral septum of wild type and AVP deficient Brattleboro rats enhances social memory, and these effects are impaired by antagonist or antisense treatments [162, 163]. The over expression of vole V1a receptors in rats enhances social discrimination abilities [164]. However, studies of V1a and V1b KO mice have had mixed results, with some reporting impaired social recognition [24, 151] and others failing to find impairments [165]. AVP has also been implicated in both memory consolidation [166] and memory retrieval [167, 168]. The social aspects of AVP's effect on memory suggest the roles of this nonapeptide in memory and affiliation are related.
