The contributions of oxytocin and vasopressin pathway genes to human behavior

Arginine vasopressin (AVP) and oxytocin (OXT) are social hormones and mediate affiliative behaviors in mammals and as recently demonstrated, also in humans. There is intense interest in how these simple nonapeptides mediate normal and abnormal behavior, especially regarding disorders of the social brain such as autism that are characterized by deficits in social communication and social skills. The current review examines in detail the behavioral genetics of the first level of human AVP-OXT pathway genes including arginine vasopressin 1a receptor (AVPR1a), oxytocin receptor (OXTR), AVP (AVP-neurophysin II [NPII]) and OXT (OXT neurophysin I [NPI]), oxytocinase/vasopressinase (LNPEP), ADP-ribosyl cyclase (CD38) and arginine vasopressin 1b receptor (AVPR1b). Wherever possible we discuss evidence from a variety of research tracks including molecular genetics, imaging genomics, pharmacology and endocrinology that support the conclusions drawn from association studies of social phenotypes and detail how common polymorphisms in AVP-OXT pathway genes contribute to the behavioral hard wiring that enables individual Homo sapiens to interact successfully with conspecifics. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.     

Molecular Variation in AVP and AVPR1a in New World Monkeys (Primates,Platyrrhini): Evolution and Implications for Social Monogamy

The neurohypophysial hormone arginine vasopressin (AVP) plays important roles in fluid regulation and vascular resistance. Differences in AVP receptor expression, particularly mediated through variation in the noncoding promoter region of the primary receptor for AVP (AVPR1a), may play a role in social phenotypes, particularly social monogamy, in rodents and humans. Among primates, social monogamy is rare, but is common among New World monkeys (NWM). AVP is a nonapeptide and generally conserved among eutherian mammals, although a recent paper demonstrated that some NWM species possess a novel form of the related neuropeptide hormone, oxytocin. We therefore characterized variation in the AVP and AVPR1a genes in 22 species representing every genus in the three major platyrrhine families (Cebidae, Atelidae and Pitheciidae). For AVP, a total of 16 synonymous substitutions were detected in 15 NWM species. No non-synonymous substitutions were noted, hence, AVP is conserved in NWM. By contrast, relative to the human AVPR1a, 66 predicted amino acids (AA) substitutions were identified in NWM. The AVPR1a N-terminus (ligand binding domain), third intracellular (G-protein binding domain), and C-terminus were variable among species. Complex evolution of AVPR1a is also apparent in NWM. A molecular phylogenetic tree inferred from AVPR1a coding sequences revealed some consensus taxonomic separation by families, but also a mixed group composed of genera from all three families. The overall dN/dS ratio of AVPR1a was 0.11, but signals of positive selection in distinct AVPR1a regions were observed, including the N-terminus, in which we identified six potential positive selection sites. AA substitutions at positions 241, 319, 399 and 409 occurred uniquely in marmosets and tamarins. Our results enhance the appreciation of genetic diversity in the mammalian AVP/AVPR1a system, and set the stage for molecular modeling of the neurohypophyseal hormones and social behavior in primates.     

The Role of OXT,OXTR, AVP,and AVPR1a Gene Expression in the Course of Schizophrenia

Schizophrenia is a serious and chronic mental illness, the symptoms of which usually appear for the first time in late adolescence or early adulthood. To date, much research has been conducted on the etiology of schizophrenia; however, it is still not fully understood. Oxytocin and vasopressin as neuromodulators that regulate social and emotional behavior are promising candidates for determining the vulnerability to schizophrenia. The aim of this study was to evaluate the expression of OXT, OXTR, AVP, and AVPR1a genes at the mRNA and protein levels in patients with schizophrenia. Due to the neurodegenerative nature of schizophrenia, the study group was divided into two subgroups, namely, G1 with a diagnosis that was made between 10 and 15 years after the onset of the illness, and G2 with a diagnosis made up to two years after the onset of the illness. Moreover, the relationship between the examined genes and the severity of schizophrenia symptoms, assessed using PANSS (Positive and Negative Syndrome Scale) and CDSS scales (Clinical Depression Scale for Schizophrenia) was evaluated. The analysis of the expression of the studied genes at the mRNA and protein levels showed statistically significant differences in the expression of all the investigated genes. OXT and AVPR1a gene expression at both the mRNA and protein levels were significantly lower in the schizophrenia group, and OXTR and AVP gene expression at both the mRNA and protein levels was higher in the schizophrenia subjects than in the controls. Furthermore, a significant correlation of OXT gene expression at the mRNA and protein levels with the severity of depressive symptoms in schizophrenia as assessed by CDSS was found.     

A complex selection signature at the human AVPR1B gene

Background  

The vasopressin receptor type 1b (AVPR1B) is mainly expressed by pituitary corticotropes and it mediates the stimulatory effects of AVP on ACTH release; common AVPR1B haplotypes have been involved in mood and anxiety disorders in humans, while rodents lacking a functional receptor gene display behavioral defects and altered stress responses.     

Tyrosinate fluorescence lifetimes for oxytocin and vasopressin in receptor-simulating environments: relationship to biological activity and 1H-NMR data

Nanosecond time-resolved tyrosinate fluorescence lifetimes were compared for oxytocin (OXT) and vasopressin (AVP) in propylene glycol. Long-lifetime tyrosinate fluorescence (LTF), characteristic of stable intramolecular hydrogen bond formation of the Tyr hydroxyl group, was present for OXT but not AVP in propylene glycol. The Tyr OH proton was also found to be labile for OXT but not AVP in DMSO by 1H-NMR. The spectroscopic data illustrate that the Tyr hydroxyl in OXT participates in an intramolecular hydrogen bond in certain receptor-simulating environments; the absence of potent LTF for [Ala5] OXT suggests that the Tyr hydroxyl of OXT forms an H-bond with the Asn5 carboxamide side-chain. The lability of the Tyr OH proton of OXT, but not AVP, is in accord with the biological activities of the peptides (OXT 100%, AVP 1%) in the rat uterus assay, suggesting that propylene glycol and DMSO mimic the environment at uterine receptors. 1H-NMR studies in DMSO demonstrate that for AVP there is a perpendicular-plate ring pairing interaction between the Tyr and Phe side-chains in which the hexagonal axis of the Tyr ring interacts with the face of the Phe ring. The present findings are discussed in terms of the proposed "cooperative model" for neurohypophysial hormone action.     

Introduction of the human AVPR1A gene substantially alters brain receptor expression patterns and enhances aspects of social behavior in transgenic mice

Central arginine vasopressin receptor 1A (AVPR1A) modulates a wide range of behaviors, including stress management and territorial aggression, as well as social bonding and recognition. Inter- and intra-species variations in the expression pattern of AVPR1A in the brain and downstream differential behavioral phenotypes have been attributed to differences in the non-coding regions of the AVPR1A gene, including polymorphic elements within upstream regulatory areas. Gene association studies have suggested a link between AVPR1A polymorphisms and autism, and AVPR1A has emerged as a potential pharmacological target for treatment of social cognitive impairments and mood and anxiety disorders. To further investigate the genetic mechanism giving rise to species differences in AVPR1A expression patterns and associated social behaviors, and to create a preclinical mouse model useful for screening drugs targeting AVPR1A, we engineered and extensively characterized bacterial artificial chromosome (BAC) transgenic mice harboring the entire human AVPR1A locus with the surrounding regulatory elements. Compared with wild-type animals, the humanized mice displayed a more widely distributed ligand-AVPR1A binding pattern, which overlapped with that of primates. Furthermore, humanized AVPR1A mice displayed increased reciprocal social interactions compared with wild-type animals, but no differences in social approach and preference for social novelty were observed. Aspects of learning and memory, specifically novel object recognition and spatial relocation recognition, were unaffected. The biological alterations in humanized AVPR1A mice resulted in the rescue of the prepulse inhibition impairments that were observed in knockout mice, indicating conserved functionality. Although further behavioral paradigms and additional cohorts need to be examined in humanized AVPR1A mice, the results demonstrate that species-specific variations in the genomic content of regulatory regions surrounding the AVPR1A locus are responsible for differential receptor protein expression patterns across species and that they are likely to contribute to species-specific behavioral variation. The humanized AVPR1A mouse is a potential preclinical model for further understanding the regulation of receptor gene expression and the impact of variation in receptor expression on behaviors, and should be useful for screening drugs targeting human AVPR1A, taking advantage of the expression of human AVPR1A in human-relevant brain regions.KEY WORDS: AVPR1A, Humanized mouse, Social behavior, Species-specific, Microsatellite, Autism     

Vasopressin regulation of the proestrous luteinizing hormone surge in wild-type and Clock mutant mice

In the female mouse, ovulation and estrous cyclicity are under both hormonal and circadian control. We have shown that mice with a mutation in the core circadian gene Clock have abnormal estrous cycles and do not have a luteinizing hormone (LH) surge on the afternoon of proestrus due to a defect at the hypothalamic level. In the present study, we tested the hypotheses that vasopressin (AVP) can act as a circadian signal to regulate the proestrous release of LH, and that this signal is deficient in the Clock mutant. We found that Avp expression in the suprachiasmatic nucleus (SCN) and AVP 1a receptor (Avpr1a) expression in the hypothalamus is reduced in Clock mutant mice compared to wild-type mice. Intracerebroventricular (i.c.v.) injection of AVP on the afternoon of proestrus is sufficient to induce LH secretion, which reaches surge levels in 50% of Clock mutant mice. The effect of AVP on the Clock mutant LH surge is mediated by AVPR1A, as co-infusion of AVP and an AVPR1A-specific antagonist prevents AVP induction of LH release, although infusion of an AVPR1A antagonist into wild-type mice failed to prevent a proestrous LH surge. These results suggest that reduced hypothalamic AVP signaling plays a role in the absence of the proestrous LH surge in Clock mutant mice. The results also support the hypothesis that AVP produced by the SCN may be a circadian signal that regulates LH release.     

Oxytocin, but not arginine vasopressin is involving in the antinociceptive role of hypothalamic supraoptic nucleus

Our pervious study has demonstrated that the hypothalamic supraoptic nucleus (SON) plays a role in pain modulation. Oxytocin (OXT) and arginine vasopressin (AVP) are the important hormones synthesized and secreted by the SON. The experiment was designed to investigate which hormone was relating with the antinociceptive role of the SON in the rat. The results showed that (1) microinjection of l-glutamate sodium into the SON increased OXT and AVP concentrations in the SON perfusion liquid, (2) pain stimulation induces OXT, but not AVP release in the SON, and (3) intraventricular injection (pre-treatment) with OXT antiserum could inhibit the pain threshold increase induced by SON injection of l-glutamate sodium, but administration of AVP antiserum did not influence the antinociceptive role of SON stimulation. The data suggested that the antinociceptive role of the SON relates to OXT rather than AVP.     

Central vasopressin administration regulates the onset of facultative paternal behavior in microtus pennsylvanicus (meadow voles)

Pharmacological experiments have implicated a role for central arginine vasopressin (AVP) in regulating paternal behavior in monogamous prairie voles. Although nonmonogamous meadow voles exhibit appreciable paternal care when housed under winter, short day lengths (SD), no research has examined whether the same neurobiological systems are involved in regulating paternal behavior in a nonmonogamous species when it behaves paternally. The goal of these experiments was to determine whether central administration of AVP, but not cerebrospinal fluid (CSF), affected the suppression of pup-directed aggression and/or the onset of paternal behavior in meadow voles. Data from experiment 1 implicated a role for AVP in facilitating changes in male behavior: central administration of 1 ng of AVP (but not 3 ng or CSF) inhibited pup-directed aggression in previously pup-aggressive males, and 3 ng of AVP (but not 1 ng or CSF) induced paternal behavior in previously nonpaternal males. In contrast, AVP (1 and 3 ng) did not enhance paternal behavior in already paternal males. Experiment 2 tested the specificity of AVP. Previous research indicated that 24 h of unmated cohabitation with a female reliably induced paternal behavior in SD males. Hence, experiment 2 examined whether administration of a V(1a) AVP antagonist (AVPA), but not CSF, prior to 24 h of unmated cohabitation would block the onset of paternal behavior. Males that received CSF displayed paternal behavior faster and engaged in more investigatory and paternal behaviors than males that received AVPA. Thus, pharmacological experiments support the hypothesis that AVP likely regulates paternal behavior in both facultatively and consistently paternal vole species.     

Prolactin promotes oxytocin and vasopressin release by activating neuronal nitric oxide synthase in the supraoptic and paraventricular nuclei

Prolactin (PRL) stimulates the secretion of oxytocin (OXT) and arginine AVP as part of the maternal adaptations facilitating parturition and lactation. Both neurohormones are under the regulation of nitric oxide. Here, we investigate whether the activation of neuronal nitric oxide synthase (nNOS) in the hypothalamo-neurohypophyseal system mediates the effect of PRL on OXT and AVP release and whether these effects operate in males. Plasma levels of OXT and AVP were measured in male rats after the intracerebroventricular injection of PRL or after inducing hyperprolactinemia by placing two anterior pituitary glands under the kidney capsule. NOS activity was evaluated in the paraventricular (PVN) and supraoptic (SON) hypothalamic nuclei by NADPH-diaphorase histochemistry and in hypothalamic extracts by the phosphorylation/inactivation of nNOS at Ser(847). Elevated central and systemic PRL correlated with increased NOS activity in the PVN and SON and with higher OXT and AVP circulating levels. Notably, treatment with 7-nitroindazole, a selective inhibitor of nNOS, prevented PRL-induced stimulation of the release of both neurohormones. Also, phosphorylation of nNOS was reduced in hyperprolactinemic rats, and treatment with bromocriptine, an inhibitor of anterior pituitary PRL secretion, suppressed this effect. These findings suggest that PRL enhances nNOS activity in the PVN and SON, thereby contributing to the regulation of OXT and AVP release. This mechanism likely contributes to the regulation of processes beyond those of female reproduction.     

Clock Gene Modulates Roles of OXTR and AVPR1b Genes in Prosociality

Background

The arginine vasopressin receptor (AVPR) and oxytocin receptor (OXTR) genes have been demonstrated to contribute to prosocial behavior. Recent research has focused on the manner by which these simple receptor genes influence prosociality, particularly with regard to the AVP system, which is modulated by the clock gene. The clock gene is responsible for regulating the human biological clock, affecting sleep, emotion and behavior. The current study examined in detail whether the influences of the OXTR and AVPR1b genes on prosociality are dependent on the clock gene.

Methodology/Principal Findings

This study assessed interactions between the clock gene (rs1801260, rs6832769) and the OXTR (rs1042778, rs237887) and AVPR1b (rs28373064) genes in association with individual differences in prosociality in healthy male Chinese subjects (n = 436). The Prosocial Tendencies Measure (PTM-R) was used to assess prosociality. Participants carrying both the GG/GA variant of AVPR1b rs28373064 and the AA variant of clock rs6832769 showed the highest scores on the Emotional PTM. Carriers of both the T allele of OXTR rs1042778 and the C allele of clock rs1801260 showed the lowest total PTM scores compared with the other groups.

Conclusions

The observed interaction effects provide converging evidence that the clock gene and OXT/AVP systems are intertwined and contribute to human prosociality.     

Maternal aggression in rodents: brain oxytocin and vasopressin mediate pup defence

The most significant social behaviour of the lactating mother is maternal behaviour, which comprises maternal care and maternal aggression (MA). The latter is a protective behaviour of the mother serving to defend the offspring against a potentially dangerous intruder. The extent to which the mother shows aggressive behaviour depends on extrinsic and intrinsic factors, as we have learned from studies in laboratory rodents. Among the extrinsic factors are the pups’ presence and age, as well as the intruders’ sex and age. With respect to intrinsic factors, the mothers’ innate anxiety and the prosocial brain neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) play important roles. While OXT is well known as a maternal neuropeptide, AVP has only recently been described in this context. The increased activities of these neuropeptides in lactation are the result of remarkable brain adaptations peripartum and are a prerequisite for the mother to become maternal. Consequently, OXT and AVP are significantly involved in mediating the fine-tuned regulation of MA depending on the brain regions. Importantly, both neuropeptides are also modulators of anxiety, which determines the extent of MA. This review provides a detailed overview of the role of OXT and AVP in MA and the link to anxiety.     

Arginine vasopressin induces periaqueductal gray release of enkephalin and endorphin relating to pain modulation in the rat

Previous study has proven that microinjection of arginine vasopressin (AVP) into periaqueductal gray (PAG) raises the pain threshold, in which the antinociceptive effect of AVP can be reversed by PAG pretreatment with V2 rather than V1 or opiate receptor antagonist. The present work investigated the AVP effect on endogenous opiate peptides, oxytocin (OXT) and classical neurotransmitters in the rat PAG. The results showed that AVP elevated the concentrations of leucine-enkephalin (L-Ek), methionine-enkephalin (M-Ek) and beta-endorphin (beta-Ep), but did not change the concentrations of dynorphinA(1-13) (DynA(1-13)), OXT, classical neurotransmitters including achetylcholine (Ach), choline (Ch), serotonin (5-HT), gamma-aminobutyric acid (GABA), glutamate (Glu), dopamine (DA), norepinephrine (NE) and epinephrine (E), and their metabolic products in PAG perfusion liquid. Pain stimulation increased the concentrations of AVP, L-EK, M-Ek, beta-Ep, 5-HT and 5-HIAA (5-HT metabolic product), but did not influence the concentrations of DynA(1-13), OXT, the other classical neurotransmitters and their metabolic products. PAG pretreatment with naloxone - an opiate receptor antagonist completely attenuated the pain threshold increase induced by PAG administration of AVP, but local pretreatment of OXT or classical neurotransmitter receptor antagonist did not influence the pain threshold increase induced by PAG administration of AVP. The data suggested that AVP in PAG could induce the local release of enkephalin and endorphin rather than dynophin, OXT and classical neurotransmitters to participate in pain modulation.     

AVPR1A Variation in Chimpanzees (Pan troglodytes): Population Differences and Association with Behavioral Style

Primates and other mammals show measurable, heritable variation in behavioral traits such as gregariousness, timidity, and aggression. Connections among behavior, environment, neuroanatomy, and genetics are complex, but small genetic differences can have large effects on behavioral phenotypes. One of the best examples of a single gene with large effects on natural variation in social behavior is AVPR1A, which codes for a receptor of the peptide hormone arginine vasopressin. Work on rodents shows a likely causal association between AVPR1A regulatory polymorphisms and social behavior. Chimpanzees also show variation in the AVPR1A regulatory region, with some individuals lacking a ca. 350-bp segment corresponding to a putative functional element. Thus, chimpanzees have a “short” allele (segment deletion) and a “long” allele (no deletion) at this locus. Here we compare AVPR1A variation in two chimpanzee populations, and we examine behavioral and hormonal data in relation to AVPR1A genotypes. We genotyped AVPR1A in a captive population of western chimpanzees (Pan troglodytes verus, New Iberia Research Center; N = 64) for which we had quantitative measures of personality (based on 15 behavioral style indices, calculated from 3 yr of observational data), dominance rank, and baseline testosterone levels. We also provide the first assessment of AVPR1A genotype frequencies in a wild eastern chimpanzee population (Pan troglodytes schweinfurthii, Ngogo community, Kibale National Park, Uganda; N = 26). Our results indicated that the AVPR1A long allele was associated with a “smart” social personality in captive western chimpanzees, independent of testosterone levels. Although the frequency of the long allele was relatively low in captive western chimpanzees (0.23), it was the major allele in wild eastern chimpanzees (0.62). Our finding that allele and genotype frequencies for the AVPR1A polymorphism differ among chimpanzee populations also highlights the need for comparative studies —across subspecies and research sites— in primate behavioral genetics.     

Electric footshocks differentially affect plasma and spinal cord vasopressin and oxytocin levels

Rats exposed for three minutes to repeated electric footshocks showed an approximate 10-fold increase of basal plasma vasopressin (AVP) and oxytocin (OXT) levels. In contrast, spinal AVP and OXT contents measured in the same rats remained unchanged when compared to undisturbed controls. This observation suggests that spinal AVP and OXT do not play a major role in the short-term adaptation of the organism to stress.     

Genetic variants in oxytocin receptor and arginine-vasopressin receptor 1A are associated with the neural correlates of maternal and paternal affection towards their child

There is extensive evidence in animal studies, particularly in vole species (Microtus), that oxytocin (OT) receptor and arginine-vasopressin (AVP) receptor 1a is critical for the regulation of maternal and paternal behavior, respectively. Human studies have gained insight into the relationship between both hormone receptor gene variants and behavior, but not between the variants and the underlying brain activity. To study this, we investigated the association between neural activation of the anterior prefrontal cortex (APFC) in mothers and fathers in response to their child smiling video stimuli to induce the positive affect related to attachment with their child, and genetic variants of OT receptor (OXTR) and AVP receptor 1A (AVPR1A). Overall, 43 mothers and 41 fathers participated, and each parent's child smiling was video recorded. Participants were then genotyped and underwent near-infrared spectroscopy to measure neural activation of the APFC while observing their own child smiling compared with an unfamiliar child. We found that the right inferior APFC was activated in response to child video stimuli in mothers and differential hemispheric activation of the inferior APFC in OXTR rs2254298-G/G mothers compared with -A carrier mothers, but not in fathers. Furthermore, we found a difference in the left inferior APFC activation between AVPR1A RS3-non-334 and -334 carrier fathers, but not mothers. Our results indicate a sex-dependent association between the genetic variants and the inferior APFC activations of maternal and paternal positive affect, analogous to the results reported in voles.     

Differential localization of vasopressin- and oxytocin-immunoreactive cells and conventional neurosecretory cells in the ganglia of the earthworm Pheretima hilgendorfi

Cells containing arginine vasopressin (AVP)- and oxytocin (OXT)-like substances were immunohistochemically visualized in the cerebral, subesophageal, and ventral nerve cord ganglia of the earthworm Pheretima hilgendorfi. Whether these anti-AVP– and anti-OXT–reactive cells are identical with classical aldehyde fuchsin (AF)-positive neurosecretory cells was tested in serial sections. In all ganglia, groups of scattered neuronal cell bodies and axons strongly reactive to AVP and OXT antisera were observed, but AF-positive cells consisting of type a (dark blue) and type b (purple) cells were predominantly present in the cerebral and subesophageal ganglia. In the cerebral and subesophageal ganglia anti-AVP– and anti-OXT–reactive cells were generally larger than AF-positive cells. Some AF-positive cells were reactive either to anti-AVP or anti-OXT serum, but some failed to react to either serum. Anti-AVP– and anti-OXT–reactive cells were not immunoreactive to OXT and AVP antisera, respectively. Electron microscopic observations showed that the granules of type a cells were larger and less electron dense than those of type b cells and anti-AVP–reactive cells. The present cytological observations clearly showed that AVP- and OXT-like substances were widely present in the ganglionic cells of the earthworm     

Oxytocin promotes functional coupling between paraventricular nucleus and both sympathetic and parasympathetic cardioregulatory nuclei

The neuropeptide oxytocin (OXT) facilitates prosocial behavior and selective sociality. In the context of stress, OXT also can down-regulate hypothalamic–pituitary–adrenal (HPA) axis activity, leading to consideration of OXT as a potential treatment for many socioaffective disorders. However, the mechanisms through which administration of exogenous OXT modulates social behavior in stressful environmental contexts are not fully understood. Here, we investigate the hypothesis that autonomic pathways are components of the mechanisms through which OXT aids the recruitment of social resources in stressful contexts that may elicit mobilized behavioral responses. Female prairie voles (Microtus ochrogaster) underwent a stressor (walking in shallow water) following pretreatment with intraperitoneal OXT (0.25 mg/kg) or OXT antagonist (OXT-A, 20 mg/kg), and were allowed to recover with or without their sibling cagemate. Administration of OXT resulted in elevated OXT concentrations in plasma, but did not dampen the HPA axis response to a stressor. However, OXT, but not OXT-A, pretreatment prevented the functional coupling, usually seen in the absence of OXT, between paraventricular nucleus (PVN) activity as measured by c-Fos immunoreactivity and HPA output (i.e. corticosterone release). Furthermore, OXT pretreatment resulted in functional coupling between PVN activity and brain regions regulating both sympathetic (i.e. rostral ventrolateral medulla) and parasympathetic (i.e. dorsal vagal complex and nucleus ambiguous) branches of the autonomic nervous system. These findings suggest that OXT increases central neural control of autonomic activity, rather than strictly dampening HPA axis activity, and provides a potential mechanism through which OXT may facilitate adaptive and context-dependent behavioral and physiological responses to stressors.     

Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine

The neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) are evolutionarily highly conserved mediators in the regulation of complex social cognition and behaviour. Recent studies have investigated the effects of OXT and AVP on human social interaction, the genetic mechanisms of inter-individual variation in social neuropeptide signalling and the actions of OXT and AVP in the human brain as revealed by neuroimaging. These data have advanced our understanding of the mechanisms by which these neuropeptides contribute to human social behaviour. OXT and AVP are emerging as targets for novel treatment approaches--particularly in synergistic combination with psychotherapy--for mental disorders characterized by social dysfunction, such as autism, social anxiety disorder, borderline personality disorder and schizophrenia.