Transient and persistent behavioral and molecular changes in primiparous female Wistar rats

Motherhood brings about a multitude of behavioral and physiological changes in dams and some of these persist until after weaning. We studied behavioral changes associated with reproductive experience at lactating day (LD)8, at weaning (LD21), and 28 days post‐weaning (PW28) compared to nulliparous (NP) females. Furthermore, in another cohort of animals, we quantified mRNA expression of five target genes known to be associated with maternal experience: arginin‐vasopressin(Avp) and its 1A receptor(Avpr1a), oxytocin(Oxt) and its receptor(Oxtr), and corticotropin‐releasing hormone(Crh) in three key maternal region: the medial preoptic area (MPOA), bed nucleus of the stria terminalis (BNST) and paraventricular hypothalamic nucleus(PVN). Although dams were slightly less anxious than NP at LD8, this effect did not persist at LD21 and PW28. No differences in social preference were found between the four groups. In the maternal responsiveness test (MRT), LD8 and LD21 dams were immediately responsive to pups whereas NP largely avoided the pups throughout 12‐day period. PW28 females were significantly more responsive to pups than NP females, but less than LD8 and LD21 females. The mRNA expression of Avp in the PVN, Avpr1a in the BNST and Oxtr in the MPOA and BNST was increased, whereas mRNA expression of Avpr1a was reduced in the PVN, at LD8 compared to NP. Although Oxtr in the BNST and Avp in the PVN were still somewhat (non‐significantly) increased at LD21, all levels of gene expression had normalized at PW28. Our results emphasize the transient nature of these behavioral and molecular adaptations, except for a persistent up‐regulation of maternal responsiveness.     

Sex‐specific mediation effect of the right fusiform face area volume on the association between variants in repeat length of AVPR1A RS3 and altruistic behavior in healthy adults

Microsatellite variants in the arginine vasopressin receptor 1A gene (AVPR1A) RS3 have been associated with normal social behaviors variation and autism spectrum disorders (ASDs) in a sex‐specific manner. However, neural mechanisms underlying these associations remain largely unknown. We hypothesized that AVPR1A RS3 variants affect altruistic behavior by modulating the gray matter volume (GMV) of specific brain regions in a sex‐specific manner. We investigated 278 young healthy adults using the Dictator Game to assess altruistic behavior. All subjects were genotyped and main effect of AVPR1A RS3 repeat polymorphisms and interaction of genotype‐by‐sex on the GMV were assessed in a voxel‐wise manner. We observed that male subjects with relatively short repeats allocated less money to others and exhibited a significantly smaller GMV in the right fusiform face area (FFA) compared with male long homozygotes. In male subjects, the GMV of the right FFA exhibited a significant positive correlation with altruistic behavior. A mixed mediation and moderation analysis further revealed both a significant mediation effect of the GMV of the right FFA on the association between AVPR1A RS3 repeat polymorphisms and allocation sums and a significant moderation effect of sex (only in males) on the mediation effect. Post hoc analysis showed that the GMV of the right FFA was significantly smaller in male subjects carrying allele 426 than in non‐426 carriers. These results suggest that the GMV of the right FFA may be a potential mediator whereby the genetic variants in AVPR1A RS3 affect altruistic behavior in healthy male subjects. Hum Brain Mapp 37:2700–2709, 2016. © 2016 Wiley Periodicals, Inc.     

Amphetamine treatment affects the extra‐hypothalamic vasopressinergic system in a sex‐ and nucleus‐dependent manner

The lateral septum (LS), a brain structure implicated in addictive behaviours, regulates the activation of dopaminergic neurones in the ventral tegmental area. Vasopressinergic projections from the extended amygdala to the LS, which are sexually dimorphic, could be responsible for the vulnerability to addiction in a sex‐dependent manner. The present study aimed to investigate the modulatory effects of amphetamine (AMPH) on the expression of vasopressin (AVP) in the vasopressinergic extra‐hypothalamic system in sensitised male and female rats. Adult male and female Sprague‐Dawley rats underwent an AMPH‐locomotor sensitisation protocol. Acute AMPH increased AVP mRNA expression in the medial amygdala (MeA), whereas AMPH‐induced sensitisation increased AVP mRNA expression in the bed nucleus of the stria terminalis (BNST) only in females. Interestingly, the increase in AVP expression in BNST was higher in oestrus females compared to dioestrus females and acute AMPH resulted in a decrease in AVP levels in the LS, only in males. Thus, there are complex and region‐specific interactions between AMPH and the extra‐hypothalamic vasopressinergic system in the brain, underlying possible alterations in different behaviours caused by acute and chronic AMPH exposure.     

Attenuated Stress Response to Acute Restraint and Forced Swimming Stress in Arginine Vasopressin 1b Receptor Subtype (Avpr1b) Receptor Knockout Mice and Wild‐Type Mice Treated with a Novel Avpr1b Receptor Antagonist

Arginine vasopressin (AVP) synthesised in the parvocellular region of the hypothalamic paraventricular nucleus and released into the pituitary portal vessels acts on the 1b receptor subtype (Avpr1b) present in anterior pituitary corticotrophs to modulate the release of adrenocorticotrophic hormone (ACTH). Corticotrophin‐releasing hormone is considered the major drive behind ACTH release; however, its action is augmented synergistically by AVP. To determine the extent of vasopressinergic influence in the hypothalamic‐pituitary‐adrenal axis response to restraint and forced swimming stress, we compared the stress hormone levels [plasma ACTH in both stressors and corticosterone (CORT) in restraint stress only] following acute stress in mutant Avpr1b knockout (KO) mice compared to their wild‐type controls following the administration of a novel Avpr1b antagonist. Restraint and forced swimming stress‐induced increases in plasma ACTH were significantly diminished in mice lacking a functional Avpr1b and in wild‐type mice that had been pre‐treated with Avpr1b antagonist. A corresponding decrease in plasma CORT levels was also observed in acute restraint‐stressed knockout male mice, and in Avpr1b‐antagonist‐treated male wild‐type mice. By contrast, plasma CORT levels were not reduced in acutely restraint‐stressed female knockout animals, or in female wild‐type animals pre‐treated with Avpr1b antagonist. These results demonstrate that pharmacological antagonism or inactivation of Avpr1b causes a reduction in the hypothalamic‐pituitary‐adrenal (HPA) axis response, particularly ACTH, to acute restraint and forced swimming stress, and show that Avpr1b knockout mice constitute a model by which to study the contribution of Avpr1b to the HPA axis response to acute stressors.     

Relationships among estrogen receptor, oxytocin and vasopressin gene expression and social interaction in male mice

The incidence of social disorders such as autism and schizophrenia is significantly higher in males, and the presentation more severe, than in females. This suggests the possible contribution of sex hormones to the development of these psychiatric disorders. There is also evidence that these disorders are highly heritable. To contribute toward our understanding of the mechanisms underlying social behaviors, particularly social interaction, we assessed the relationship of social interaction with gene expression for two neuropeptides, oxytocin (OT) and arginine vasopressin (AVP), using adult male mice. Social interaction was positively correlated with: oxytocin receptor (OTR) and vasopressin receptor (V1aR) mRNA expression in the medial amygdala; and OT and AVP mRNA expression in the paraventricular nucleus of the hypothalamus (PVN). When mice representing extremes of social interaction were compared, all of these mRNAs were more highly expressed in high social interaction mice than in low social interaction mice. OTR and V1aR mRNAs were highly correlated with estrogen receptor α (ERα) mRNA in the medial amygdala, and OT and AVP mRNAs with estrogen receptor β (ERβ) mRNA in the PVN, indicating that OT and AVP systems are tightly regulated by estrogen receptors. A significant difference in the level of ERα mRNA in the medial amygdala between high and low social interaction mice was also observed. These results support the hypothesis that variations of estrogen receptor levels are associated with differences in social interaction through the OT and AVP systems, by upregulating gene expression for those peptides and their receptors.     

Oestrogen‐Independent Circadian Clock Gene Expression in the Anteroventral Periventricular Nucleus in Female Rats: Possible Role as an Integrator for Circadian and Ovarian Signals Timing the Luteinising Hormone Surge

Periodic ovulation in rats, mice and hamsters is the result of a surge in luteinising hormone (LH) that depends on circadian gating signals emerging from the master circadian clock within the suprachiasmatic nucleus (SCN) and rising ovarian oestrogen levels. These two signals converge into the anteroventral periventricular nucleus (AVPV) and lead to the release of kisspeptin, which is responsible for surges of gonadotrophin‐releasing hormone and, in turn, of LH release. How the AVPV integrates circadian and reproductive signals remains unclear. In the present study, we show that the female rat AVPV itself shows circadian oscillations in the expression of the clock genes PER1 and BMAL1, which lie at the core circadian clockwork of mammals. In ovariectomised females treated with oestradiol (E₂), these oscillations are in synchrony with the AVPV rhythmic expression of the KISS1 gene and the gene that codes for the arginine‐vasopressin (AVP) receptor AVPr1a. Although clock gene oscillations are independent of oestrogen levels, circadian expression of Kiss1 and Avpr1a (also referred to as V1a) mRNA is blunted and absent, respectively, in ovariectomised animals without E₂ replacement. Because AVP is considered to be a critical SCN transmitter to gate the LH surge, our data suggest that there is a circadian oscillator located in the AVPV, and that such a putative oscillator could, in an oestrogen‐dependent manner, time the sensitivity to circadian signals emerging from the SCN and the release of kisspeptin.     

Pituitary-adrenal response to acute and repeated mild restraint, forced swim and change in environment stress in arginine vasopressin receptor 1b knockout mice

Arginine vasopressin and corticotrophin-releasing hormone synthesised and released from the hypothalamic paraventricular nucleus are the prime mediators of the hypothalamic-pituitary-adrenal (HPA) axis response to stress. These neurohormones act synergistically to stimulate adrenocorticotophin (ACTH) secretion from the anterior pituitary, culminating in an increase in circulating glucocorticoids. Arginine vasopressin mediates this action at the arginine vasopressin 1b receptor (Avpr1b) located on pituitary corticotrophs. Arginine vasopressin is regarded as a minor ACTH secretagogue in rodents but evidence suggests that it has a role in mediating the neuroendocrine response to some acute and chronic stressors. To investigate the role of the Avpr1b in the HPA axis response to an acute and chronic (repeated) stress, we measured the plasma ACTH and corticosterone concentrations in three stress paradigms in both Avpr1b knockout and wild-type mice. Single acute exposure to restraint, forced swim and change in environment stressors elevated both plasma ACTH and corticosterone concentrations in wild-type animals. Conversely, the ACTH response to the acute stressors was significantly attenuated in Avpr1b knockout mice compared to their wild-type counterparts. Plasma corticosterone concentrations were reduced in Avpr1b knockout mice in response to change in environment but not to mild restraint or forced swim stress. Irrespective of genotype, there was no difference in the plasma ACTH or corticosterone concentrations in response to acute and repeated stressors. The data show that a functional Avpr1b is required for an intact pituitary ACTH response to the acute and chronic stressors used in this study. Furthermore, the normal corticosterone response to repeated exposure to change in environment stress also requires the Avpr1b to drive HPA axis responsiveness.     

Androgen and Estrogen Effects on Vasopressin Messenger RNA Expression in the Medial Amygdaloid Nucleus in Male and Female Rats

Vasopressin messenger RNA (AVP mRNA) expression in the medial amygdala and bed nucleus of the stria terminalis (BST) is almost completely dependent on gonadal steroids. In the BST, the effects of gonadal steroids on AVP mRNA expression are sexually dimorphic. Males have more cells that express AVP mRNA and more AVP mRNA per cell than females. Here we test whether this is also true for the MA. In gonadectomized rats that were treated with testosterone, males had more cells that were labeled for AVP mRNA than females. However, the labeling per cell did not differ between males and females. To assess contribution of testosterone metabolites to these differences, male and female rats were gonadectomized and implanted with empty tubing, or tubing filled with dihydrotestosterone (DHT), estradiol (E), or E plus DHT (E + DHT). The pattern of steroid effects on AVP mRNA expression in the MA was similar in both sexes. Hardly any labeled cells were found in rats with empty implants or rats treated with DHT. Significantly more labeled cells were found in rats treated with E, and even more cells in rats treated with E + DHT. The number of AVP mRNA-labeled cells was higher in males than in females for E as well as E + DHT treatment, but the labeling per cell did not differ between sexes. These data suggest that the number of MA cells that can express AVP mRNA is higher in males than in females, but the estrogen and androgen responsiveness of individual AVP mRNA-expressing cells in the MA does not differ between sexes.     

Sexual dimorphism in the vasopressin system: lack of an altered behavioral phenotype in female V1a receptor knockout mice

Previous findings with an AVP V1a receptor knockout mouse (V1aRKO) demonstrate a significant role for this receptor in anxiety-like behavior in males. Here we report the lack of anxiety-like effects of the null mutation in female mice. V1aRKO females performed normally on all tests for anxiety-like behavior. This sex difference may be due to the sexual dimorphism in the extra-hypothalamic vasopressin system, with males having significantly more vasopressin fibers in this system.     

Localization of vasopressin (V1a) receptor binding and mRNA in the rhesus monkey brain

Centrally released arginine vasopressin (AVP) has been associated with various behavioural and cognitive effects, such as scent marking, aggression, and memory, which are believed to be mediated by the V1a subtype of the vasopressin receptor. Although the distribution of V1a receptors is conserved in a few brain regions, the pattern of expression of this receptor is, in general, highly species-specific. We have used receptor autoradiography with the linear V1a receptor ligand (125I-Phenylacetyl-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2) to characterize the pattern of receptor binding in the rhesus monkey brain. Brain sites of V1a receptor synthesis were defined using in-situ hybridization. The regions of highest V1a receptor density included the prefrontal, cingulate, pyriform, and entorhinal cortex, as well as the presubiculum and mamillary bodies. In addition, V1a receptor binding and mRNA were detected in several regions reported to have V1a receptor in most rodents, including the amygdala, bed nucleus of the stria terminalis, lateral septum, hypothalamus and the brainstem. The distribution is consistent with a role for vasopressin in higher cognitive functions, especially memory, in primates.     

Further genetic evidence implicates the vasopressin system in childhood-onset mood disorders

Studies in both animals and humans advocate a role for the vasopressin (AVP) system in the aetiology of depressive symptoms. Attention has particularly focused on the role of AVP in the overactivation of the hypothalamic-pituitary-adrenal (HPA)-axis in mood disorders. Elevated AVP plasma levels have been found in mood disorder patients, which are often positively correlated with the severity of symptoms. We recently reported an association between childhood-onset mood disorders (COMD) and polymorphisms in the receptor responsible for the AVP-mediated activation of the HPA-axis ( AVPR1B ). As genetic variation in the vasopressinergic system could provide a mechanism to explain the endocrine alterations observed in mood disorders, we investigated other genes in this system. The gene encoding AVP is the strongest candidate, particularly as genetic variation in this gene in rodents is associated with anxiety-related behaviours. Six single-nucleotide polymorphisms (SNPs) were genotyped across the AVP gene in a sample comprised of 586 Hungarian nuclear families ascertained through affected probands with a diagnosis of COMD. In addition, AVP coding and putative regulatory regions were screened for mutations using denaturing high-performance liquid chromatography. One SNP, 3' to the AVP, gene reached significance ( P  =   0.03), as did the overtransmission of a five-marker haplotype with a frequency of 22% ( P  =   0.0001). The subsequent mutation screen failed to identify any putative functional polymorphisms. The outcome of this study, combined with our previous association between COMD and AVPR1B , implicates genetic variation in vasopressinergic genes in mediating vulnerability to COMD.     

Hypothalamic Neurosecretory and Circadian Vasopressinergic Neuronal Systems in the Blind Cone‐Rod Homeobox Knockout Mouse (Crx−/−) and the 129sv Wild‐Type Mouse

Vasopressin (AVP) is both a neuroendocrine hormone located in magnocellular neurosecretory neurons of the hypothalamus of mammals but also a neurotransmitter/neuromodulator in the parvocellular suprachiasmatic nucleus (SCN). The SCN is the endogenous clock of the brain and exhibits a prominent circadian AVP rhythm. We have in this study of the brown 129sv mouse and the visual blind cone–rod homeobox gene knock out mouse (Crx^?/?) with degeneration of the retinal rods and cones, but a preserved non‐image forming optic system, studied the temporal Avp expression in both the neurosecretory magnocellular and parvocellular vasopressinergic systems in both genotypes. We here present a detailed mapping of all classical hypothalamopituitary and accessory magnocellular nuclei and neurons in the hypothalamus by use of immunohistochemistry and in situ hybridization in both genotypes. Semiquantitative in situ hybridization revealed a very high expression of Avp mRNA in all the magnocellular nuclei compared with a much lower level in the parvocellular suprachiasmatic nucleus. In a series of mice killed every 4 hours, the Avp mRNA expression in the SCN showed a significant daily rhythm with a zenith at late day time and nadir during the dark in both the Crx^?/? and the wild type mouse. None of the magnocellular neurosecretory neurons exhibited a diurnal vasopressin expression. Light stimulation of both genotypes during the dark period did not change the Avp expression in the SCN. This shows that Avp expression in the mouse SCN is independent of Crx‐regulated photoreceptor systems. J. Comp. Neurol. 521:4061–4074, 2013. © 2013 Wiley Periodicals, Inc.     

精氨酸加压素受体和催产素受体基因多态性与男性青少年暴力攻击行为的关联研究

目的:探讨精氨酸加压素受体(AVPR1A、AVPR1B)和催产素受体(OXTR)基因多态性在青少年男性暴力攻击行为发生中的作用,并进一步分析基因与基因的交互作用。方法:采用SNa Pshot基因分型技术对138名暴力攻击行为男性少教人员(暴力组)、98名非暴力男性少教人员(非暴力组)以及153名正常成年男性(正常组)的AVPR1A(rs1042615)、AVPR1B(rs28632197)、OXTR(rs13316193、rs2254298、rs53576、rs2268498、rs237885)进行基因分型检测,分析3组间的等位基因和基因型频率。采用多因子降维法(MDR)构建影响暴力攻击行为发生的基因-基因间交互作用模型。结果:暴力组AVPR1B基因rs28632197位点A等位基因频率明显高于非暴力组和正常组(P均0.017),OR值分别为2.24及2.63,95%CI分别为(1.45~3.47)和(1.78~3.88);暴力组与非暴力组及正常组在基因型分布差异有统计学意义(P0.05),暴力组含A等位基因的基因型(AA/AG)明显高于非暴力组和正常组(P0.017);其余位点组间差异无统计学意义。AVPR1B(rs28632197)与OXTR(rs53576)在暴力攻击行为的发生中存在基因间交互作用。结论:AVPR1B基因多态性可能与暴力攻击行为相关;AVPR1B与OXTR基因的交互作用可能增加暴力攻击行为的发生风险。     

Effects of dehydration and salt-loading on hypothalamic vasopressin mRNA level in male and female rats

Experiments were carried out on 9- to 11-week-old male and female Sprague-Dawley rats. Dot-blot analysis and 3′-end digoxigenin-labeled 26mer oligonucleotide probe were used in the investigation of vasopressin (AVP) mRNA level in the hypothalamus of male and female rats. The normal hypothalamic AVP-mRNA level in males was 48% higher than that in females (P < 0.05). Plasma osmolality was also higher in males than in females (P < 0.05). In dehydrated rats, the hypothalamic AVP-mRNA level was 2.47 and 1.98 times in females (P < 0.001) and males (P < 0.01), respectively, as much as in their normal controls; the difference in hypothalamic AVP-mRNA level between dehydrated females and males was statistically insignificant. Plasma osmolality was higher in dehydrated females than in dehydrated males (P < 0.01). In salt-loaded rats, hypothalamic AVP-mRNA level was 2.47 and 2.17 times in females (P < 0.001) and males (P < 0.01), respectively, as much as in their controls. The difference in hypothalamic AVP-mRNA level between salt-loaded males and females was not statistically significant. Plasma osmolality in salt-loaded females was also higher than that in salt-loaded males (P < 0.001). These findings indicate that there is sex difference in hypothalamic AVP mRNA level and plasma osmolality under normal conditions; during dehydration and salt-loading AVP mRNA level increases and the difference in AVP mRNA level between males and females becomes insignificant.     

Central Endogenous Vasopressin Induced by Central Salt-Loading Participates in Body Fluid Homeostasis through Modulatory Effects on Neurones of the Paraventricular Nucleus in Conscious Rats

Peripherally secreted arginine vasopressin (AVP) plays a role in controlling body fluid homeostasis, and central endogenous AVP acts as a neurotransmitter or neuromodulator. The limbic system, which appears to exert an inhibitory effect on the endocrine hypothalamus, is also innervated by fibres that contain AVP. We examined whether central endogenous AVP is also involved in the control of body fluid homeostasis. To explore this possibility, we examined neuronal activity in the paraventricular nucleus of the hypothalamus (PVN), periventricular parts of the PVN and limbic brain areas, as well as AVP mRNA expression in the PVN and the peripheral secretion of AVP after central salt-loading in rats that had been pretreated i.c.v. with the AVP V₁ receptor antagonist OPC-21268. Neuronal activity in the PVN evaluated in terms of Fos-like immunoreactivity (FLI), especially in the parvocellular subdivisions, was suppressed. On the other hand, FLI was enhanced in the lateral septum, the bed nucleus of the stria terminalis and the anterior hypothalamic area. Similarly, AVP mRNA expression was enhanced in the magnocellular subnucleus of the PVN, despite the lack of a significant difference in the peripheral AVP level between OPC-21268- and vehicle-pretreated groups. We recorded renal sympathetic nerve activity (RSNA) as sympathetic nerve outflow during central salt-loading. The suppression of RSNA was significantly attenuated by i.c.v. pretreatment with OPC-21268. These results suggest that the suppression of RSNA during central salt-loading might be the result of a decrease in neuronal activity in the parvocellular subdivisions of the PVN via the inhibitory action of central endogenous AVP. The parvocellular and magnocellular neurones in the PVN might show different responses to central salt-loading to maintain body fluid homeostasis as a result of the modulatory role of central endogenous AVP.     

Sex Differences in the Expression of Sex Steroid Receptor mRNA in the Quail Brain

In Japanese quail, males will readily exhibit the full sequence of male‐typical sexual behaviors but females never show this response, even after ovariectomy and treatment with male‐typical concentrations of exogenous testosterone. Testosterone aromatisation plays a key‐limiting role in the activation of this behavior but the higher aromatase activity in the brain of males compared to females is not sufficient to explain the behavioural sex difference. The cellular and molecular bases of this prominent sex difference in the functional consequences of testosterone have not been identified so far. We hypothesised that the differential expression of sex steroid receptors in specific brain areas could mediate this behavioural sex difference. Therefore, using radioactive in situ hybridisation histochemistry, we quantified the expression of the mRNA coding for the androgen receptor (AR) and the oestrogen receptors (ER) of the α and β subtypes. All three receptors were expressed in an anatomically discrete manner in various nuclei of the hypothalamus and limbic system and, at usually lower densities, in a few other brain areas. In both sexes, the intensity of the hybridisation signal for all steroid receptors was highest in the medial preoptic nucleus (POM), a major site of testosterone action that is related to the activation of male sexual behaviour. Although no sex difference in the optical density of the AR hybridisation signal could be found in POM, the area covered by AR mRNA was significantly larger in males than in females, indicating a higher overall degree of AR expression in this region in males. By contrast, females tended to have significantly higher levels of AR expression than males in the lateral septum. ERα was more densely expressed in females than males throughout the medial preoptic and hypothalamic areas (including the POM and the medio‐basal hypothalamus), an area implicated in the control of female receptivity) and in the mesencephalic nucleus intercollicularis. ERβ was more densely expressed in the medio‐basal hypothalamus of females but a difference in the reverse direction (males > females) was observed in the nucleus taeniae of the amygdala. These data suggest that a differential expression of steroid receptors in specific brain areas could mediate at least certain aspects of the sex differences in behavioural responses to testosterone, although they do not appear to be sufficient to explain the complete lack of activation by testosterone of male‐typical copulatory behaviour in females.     

Effects of neonatal treatment with valproic acid on vasopressin immunoreactivity and olfactory behaviour in mice

Recent findings demonstrate that epigenetic modifications are required for the sexual differentiation of the brain. For example, neonatal administration of the histone deacetylase inhibitor, valproic acid, blocks masculinisation of cell number in the principal nucleus of the bed nucleus of the stria terminalis (BNST). In the present study, we examined the effects of valproic acid on neurochemistry and behaviour, focusing on traits that are sexually dimorphic and linked to the BNST. Newborn mice were treated with saline or valproic acid and the effect on vasopressin immunoreactivity and olfactory preference behaviour was examined in adulthood. As expected, males had more vasopressin immunoreactive fibres than females in the lateral septum and medial dorsal thalamus, which are two projection sites of BNST vasopressin neurones. Neonatal valproic acid increased vasopressin fibre density specifically in females in the lateral septum, thereby reducing the sex difference, and increased vasopressin fibres in both sexes in the medial dorsal thalamus. The effects were not specific to BNST vasopressin projections, however, because valproic acid also significantly increased vasopressin immunoreactivity in the anterior hypothalamic area in both sexes. Subtle sex-specific effects of neonatal valproic acid treatment were observed on olfactory behaviour. As predicted, males showed a preference for investigating female-soiled bedding, whereas females showed a preference for male-soiled bedding. Valproic acid did not significantly alter olfactory preference, per se, although it increased the number of visits females made to female-soiled bedding and the overall time females spent investigating soiled versus clean bedding. Taken together, these results suggest that a transient disruption of histone deacetylation at birth does not have generalised effects on sexual differentiation, although it does produce lasting effects on brain neurochemistry and behaviour.     

Transmission disequilibrium testing of arginine vasopressin receptor 1A (AVPR1A) polymorphisms in autism

Impairment in social reciprocity is a central component of autism. In preclinical studies, arginine vasopressin (AVP) has been shown to increase a range of social behaviors, including affiliation and attachment, via the V(1a) receptor (AVPR1A) in the brain. Both the behavioral effects of AVP and the neural distribution of the V1a receptor vary greatly across mammalian species. This difference in regional receptor expression as well as differences in social behavior may result from a highly variable repetitive sequence in the 5' flanking region of the V1a gene (AVPR1A). Given this comparative evidence for a role in inter-species variation in social behavior, we explored whether within our own species, variation in the human AVPR1A may contribute to individual variations in social behavior, with autism representing an extreme form of social impairment. We genotyped two microsatellite polymorphisms from the 5' flanking region of AVPR1A for 115 autism trios and found nominally significant transmission disequilibrium between autism and one of the microsatellite markers by Multiallelic Transmission/Disequilibrium test (MTDT) that was not significant after Bonferroni correction. We also screened approximately 2 kb of the 5' flanking region and the coding region and identified 10 single nucleotide polymorphisms.     

Dissociation of the anxiolytic-like effects of Avpr1a and Avpr1b receptor antagonists in the dorsal and ventral hippocampus

Arginine-vasopressin (AVP) is synthesized and released centrally in several brain structures. AVP is thought to mediate anxiety-related behavior through two central receptor subtypes, Avpr1a and Avpr1b. Although these AVP receptor subtypes are expressed in several brain regions, including the hippocampus, little is known about their explicit role in unconditioned fear or anxiety. This experiment assessed the anxiety-related effects of a selective Avpr1a antagonist ([beta-Mercapto-beta,beta-cyclopentamethylenepropionyl1, O-me-Tyr2, Arg8]-AVP) and a selective Avpr1b antagonist ((2S,4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine carboxamide; SSR 149415) microinfused into either the dorsal or ventral sub-regions of the rat hippocampus. Avpr1a antagonism in the ventral, but not the dorsal hippocampus reduced rats' anxiety-like behavior in the elevated plus-maze test. Conversely, Avpr1b antagonism in the dorsal, but not the ventral, hippocampus reduced anxiety in the plus-maze test. Neither antagonist reduced anxiety-like behavior in the shock-probe burying test. Overall, the results show that both receptor subtypes of AVP are involved in anxiety-related responses, but their specific contributions depend on three variables: (1) the anxiety-related response (shock-probe avoidance versus open-arm avoidance), (2) the receptor subtype antagonized (Avpr1a versus Avpr1b), and (3) the area of hippocampus (dorsal versus ventral) into which these antagonists are infused. These dissociations suggest that different fear responses are under the control of specific AVP receptor systems within discrete parts of the hippocampus.