**8. AVP in male humans**

60 Neuroendocrinology and Behavior

**7. AVP in female animals** 

**7.1. AVP and female animal affiliation** 

**7.2. AVP and female animal aggression** 

increased durations of aggressive bouts [175].

**7.3. AVP and animal maternal behavior** 

Most of the work on AVP and pairbonding in voles has focused on the male vole. Several studies indicate that OXT is more important than AVP for female pair bonding [169]. It is known that OXT receptor and AVP V1a antagonists prevent pair bond formation in both males and females [170]. Studies of AVP and maternal behavior indirectly support the hypothesis that AVP is a mediator of female affiliation [48, 171], but it is unknown if these effects pertain to adult conspecific affiliation. Additional studies on females are needed to determine if central

Several studies have reported that AVP has inhibitory effects on maternal aggression towards a male intruder, which contrasts with the stimulatory role of AVP in male rodent aggression. V1a antagonist treatment increases maternal aggression in both primiparous and multiparous dams, and AVP injection decreases maternal aggression in highly aggressive multiparous rats [171, 172]. An inhibitory role for AVP in females is also supported by multiple experiments in non-maternal female hamsters [173]. Gene expression analysis of primiparous and multiparous rats indicates that changes in both AVP and OXT may be involved in the parity associated increase in maternal aggression in multiparous rats, as high levels of aggression are associated with low levels of AVP and OXT activity in several nuclei [45]. fMRI study of the neural effects of V1a antagonist treatment during the presentation of a novel male intruder reveal that this treatment may increase aggressive responding by enhancing the somatosensory responses to a male intruder and reducing fear responses in the cortical amygdala and ventromedial hypothalamus [174]. One hypothesis derived from these data is that AVP increases the perceived threat from the male intruder. Although some studies have found increased AVP release associated with maternal aggression, it is hypothesized that this release is triggered by the stressful nature of the encounter [36]. Manipulations of AVP in rat strains selected for anxiety behaviors reveal an excitatory function of AVP on aggression, but this effect on aggression only involves behavioral frequencies, and it is not known if the decreased frequencies are associated with

Recent studies indicate that OXT is not the only nonapeptide involved in the modulation of mammalian maternal care. Both AVP and V1a antagonist treatments decrease maternal care during exposure to a male intruder, with the effects of AVP associated with increased self grooming and the effects of V1a antagonist associated with elevated maternal aggression during resident intruder tests of maternal aggression [171]. Studies focusing specifically on maternal care conclude that central AVP promotes ongoing maternal care [48]. Furthermore, the blockade of V1a receptors around parturition impairs maternal memory, the ability of a

AVP also is a significant mediator of the female component of pairbonding.

#### **8.1. AVP and male human affiliation**

Intranasal AVP has been reported to enhance the encoding of emotional facial expressions in humans [179], as well as improving the recognition of sexual cues [180]. Other studies

indicate that intranasal AVP increases the negative emotional response to neutral facial expressions [181, 182]. These effects appear to be gender specific, as intranasal AVP in men stimulates agonistic responses to the faces of novel men, but stimulates affiliative facial responses in women and increases positive perceptions of these faces [181]. AVP increases cooperative behavior in men in response to a cooperative gesture in a social experiment, and this behavioral effect was associated with fMRI activity in brain regions involved in affiliative responses [74]. It has been suggested that plasma AVP may be a biomarker of distressed relationships in men [105]. Similar to several other behavioral topics, these gender specific effects need to be considered with respect to treatment development.

Behavioral Roles of Oxytocin and Vasopressin 63

**9. AVP in female humans** 

**9.1. AVP and female human affiliation** 

**9.2. AVP and human maternal behavior** 

neglect associated mood disorders.

depression and anxiety.

**10.1. Stress** 

**10. Translation from animals to humans** 

**9.3. AVP and female human female depression and anxiety** 

In contrast to the pro-aggressive effects of intranasal AVP in men, AVP induces affiliative facial motor patterns in women in response to the faces of unfamiliar women and increases the perception of the faces as friendly. This gender specific effect supports the animal work on AVP. In contrast, the AVP treatment increased anxiety in both sexes [181]. Homozygosity for the RS3 allele 334 doubles the risk of marital difficulties, and negatively influenced how the relationship was perceived by the spouse [203]. Central AVP activity may be a worthwhile target for gender specific treatments aimed at improving human pair bonds.

Studies of multiparous humans report that maternal sensitivity is associated with the AVP V1a receptor gene. Mothers with 2 copies of the long RS3 alleles were less sensitive than mothers with one or zero copies of the long allele, and this association was most prevalent in mothers exposed to high maternal adversity [204]. A valid question is how this polymorphism affects affiliation in females, as in the Walum et al. 2008 study. Exposure to maternal neglect is associated with depressed urinary AVP levels in children [205]. The effects were persistent despite being in a stable environment for three years following the maternal neglect. It was concluded that social deprivation inhibits the long-term development of the central AVP system, and this effect may be involved in the etiology of

Much of the research on this topic is focused on the interaction between stress, AVP, and depression. Specific V1b receptor haplotypes are associated with protection against recurrent major depression in both males and females [193]. A more recent study has found the association between V1b gene variants, AVP single nucleotide polymorphisms (SNP's), and vulnerability to childhood onset depression in females [206, 207]. In a study of male and female depression patients, plasma AVP was highly correlated with depression in nontreated patients, but this correlation was not found in patients taking anti-depressants [191]. These studies suggest that the central AVP system is a valid target for treatments for

There is a great deal of translational overlap in the research areas where focus on AVP and OXT is most relevant, and this is especially true with the studies on the effects of stress. Exposure to acute and/or chronic stress is often a predictor of depression/anxiety, addiction relapse, and relationship difficulties. It is suggested that the most valuable paradigms for
