V1b Receptor Research Articles

Arginine Vasopressin Gene Variation and Behavioural Inhibition in Children: an Exploratory Study

Behavioural inhibition (BI) refers to a temperamental style of responding to unfamiliar people, objects, contexts and challenging situations with cautious, avoidant and restrained behaviour. Several lines of evidence suggest that variation in the genes of the arginine vasopressin system may be candidate genes for BI. We examined associations between BI and a total of eight single‐nucleotide polymorphisms (SNPs) across the arginine vasopressin (AVP) gene, the arginine vasopressin 1a (AVPR1A) receptor gene, and the arginine vasopressin 1b (AVPR1B) receptor gene. The sample consisted of 337 families from whom BI was coded from direct observation with two typically developing children per family. We performed single‐marker analysis, and we also tested the combination of alleles, the haplotypes, for each gene for association with BI. Results revealed that SNP rs3761249 in the AVP gene region showed a significant association between allele C and BI measures. No other significant associations were found between BI and the other seven SNPs and haplotypes. The present exploratory study provides the first empirical evidence of a possible association between behavioural inhibition and variation in the AVP gene in humans. Findings are discussed within the context of vasopressin's influence on individual differences in social behaviour. Copyright © 2014 John Wiley & Sons, Ltd.

Effect of combined V1a/V1b vasopressin receptor blockade within the paraventricular nucleus on neurocardiovascular responses (1130.2)

The paraventricular nucleus (PVN) plays a critical role vasopressin (AVP) secretion by the neurohypophysis. AVP released from dendrites of magnocellular neurons within PVN influences systemic hemodynamics and renal sympathetic nerve activity (RSNA). Both V1a and V1b receptors exist on PVN neurons. We have shown that inhibition of either of these receptors alone blocks the rise in MAP and RSNA in response to AVP. We tested the hypothesis that combined subthreshold doses of V1a and V1b blockers within the PVN will inhibit AVP‐induced increases in MAP and RSNA. Studies were performed in awake, unrestrained,chronically instrmented male Sprague Dawley rats. Microinjection of 100 ng AVP into the PVN increased MAP 18.2±3.1 mmHg (P<0.001) while heart rate and RSNA decreased 52±21 bpm and 26.8±10.6%baseline, respectively (P<0.05). The response to combined subthreshold inhibitory doses of Manning compound (V1a, 20 ng) and nelivaptan (V1b, 0.5 ng) resulted in a significant attenuation of the rise in MAP, 13.3±3.2 mmHg, and attenuation of the reflex decrease in heart rate, 12±8 bpm, and RSNA, 7.2±4.6%baseline. Vehicle did not block any of the responses. These findings suggest that V1a and V1b activated pathways both participate and may interact to induce the pressor and sympathoexcitatory response to AVP within the PVN.Grant Funding Source: VA Merit Award

Characterization of a novel vasopressin V1b receptor antagonist, V1B-30N, in animal models of anxiety-like and depression-like behavior

Overactivity of the hypothalamic–pituitary–adrenal (HPA) axis has been linked to affective disorders such as anxiety and depression. Dampening HPA activity has, therefore, been considered as a possible means of treating affective disorders. Given the important role of vasopressin in modulating the HPA axis, one strategy has focused on inhibiting activity of the vasopressin 1b (V1b) receptor. In animals, V1b receptor antagonists reduce plasma stress hormone levels and have been shown to have an anxiolytic-like effect. Recently, V1B-30N was identified as a highly potent V1b receptor antagonist with selectivity over other vasopressin receptors, which is evaluated here in rodent models of anxiety-like and depression-like behaviors. V1B-30N (1–30mg/kg, IP) dose-dependently reduced separation-induced vocalizations in rat pups without producing any sedative effects in the animals. Similarly, V1B-30N (3–30mg/kg, IP) dose-dependently reduced separation-induced vocalizations in guinea pig pups. In a conflict assay, conditioned lick suppression, V1B-30N (3–30mg/kg, IP) increased punished licking. To assess antidepressive-like properties, V1B-30N (1–30mg/kg) was tested in the mouse and rat forced-swim tests but was found to be inactive. These results are consistent with previous findings with other V1b antagonists, which suggest that acute pharmacological antagonism of the V1b receptor has anxiolytic-like but not antidepressant-like properties.

Arginine-vasopressin receptor gene (AVPR1A, AVPR1B) polymorphisms and their relation to personality traits

The present study aimed to assess the main effects ofAVPRIA (rs11174811, RSI) and AVPRIB (rs28632197, rs33911258) gene polymorphisms, as well as haplotypic, GxE and GxG effects on personality trait variation in 1018 healthy individuals, considering gender and ethnicity confounding. Haplotype analysis revealed an association ofAVPRIA C*S- and C*L-haplotype (rs11174811 and RS1, respectively) and increased (PFDR= 0.016) or decreased (PFDR = 0.031) Extraversion (EPI) in Bashkirs, respectively. The association of AVPR1B G*A-haplotype (rs28632197 and rs33911258, respectively) and decreased Self-transcendence (TCI-125) (P(FDR) = 0.040) was demonstrated in the total sample and in Udmurts. GxE analysis revealed that the birth season modulated the involvement of the AVPR1A (rs11174811) gene marker in the variation of Persistence (TCI-125) in the total sample (P(FDR) = 0.012). The modulating effect of several environmental factors (ethnicity and birth season) on the association of AVPR1A and AVPR1B gene polymorphisms and personality traits was established.

The hypothalamic–neurohypophysial system: genomes, genes and genetics

The hypothalamic–neurohypophysial system: genomes, genes and genetics

Mechanisms Underlying the Increased Plasma ACTH Levels in Chronic Psychosocially Stressed Male Mice

Mice exposed to chronic subordinate colony housing (CSC, 19 days), an established paradigm for chronic psychosocial stress, show unaffected basal morning plasma corticosterone (CORT) concentrations, despite enlarged adrenal glands and an increased CORT response to an acute heterotypic stressor. In the present study we investigate the mechanisms underlying these phenomena at the level of the pituitary. We show that both basal and acute stressor-induced (forced swim (FS), 6 min) plasma adrenocorticotropic hormone (ACTH) concentrations, the number of total and corticotroph pituitary cells, and relative protein expression of pituitary mineralocorticoid receptor and FK506-binding protein 51 was increased in CSC compared with single-housed control (SHC) mice, while relative corticotropin releasing hormone (CRH) receptor 1 (CRH-R1) and glucocorticoid receptor protein expression was down-regulated. Relative pituitary pro-opiomelanocortin and arginine vasopressin (AVP) receptor 1b (AVPR-1b) protein expression, FS (6 min)-induced ACTH secretion in dexamethasone-blocked mice, and the number of AVP positive magnocellular and parvocellular neurons in the paraventricular hypothalamic nucleus (PVN) was unaffected following CSC. Taken together, the data of the present study indicate that 19 days of CSC result in pituitary hyperactivity, under both basal and acute heterotypic stress conditions. Although further studies have to assess this in detail, an increased number of pituitary corticotrophs together with unaffected relative pituitary AVPR-1b and decreased CRH-R1 protein expression following CSC suggests that pituitary hyperdrive is mediated by newly formed corticotrophs that are more sensitive to AVP than CRH. Moreover, our data indicate that changes in PVN AVP and negative feedback inhibition seem not to play a major role in pituitary hyperactivity following CSC.

Epistatic interaction between CRHR1 and AVPR1b variants as a predictor of major depressive disorder

Genes involved in the regulation of the hypothalamus-pituitary-adrenal axis are responsible for altered susceptibility to mood disorders. The aim of this study was to analyze the possible association of CRHR1 and AVPR1b gene variants with bipolar disorder and major depressive disorder (MDD). In the study, we included 486 patients with bipolar disorder and 215 patients with MDD. Consensus diagnosis was made according to Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria, using the Structured Clinical Interview for DSM Disorders. The control group consisted of 712 healthy participants. Genotyping of CRHR1 and AVPR1b polymorphisms was performed using TaqMan single nucleotide polymorphism genotyping assays. Linkage disequilibrium analysis was carried out on Haploview. Gene-gene interactions were analyzed using the multifactor dimensionality reduction method. By single marker analysis we have found an association of rs28536160 of AVPR1b and rs4076452 and rs16940655 of CRHR1 with mood disorders (P=0.036, 0.0013, and 0.003, respectively). We observed strong linkage disequilibrium between seven CRHR1 polymorphisms grouped in two haplotype blocks; however, none of them showed an association with MDD or bipolar disorder. Similarly, no association was found for three of four strongly linked AVPR1b polymorphisms. Gene-gene interaction analysis revealed a significant epistatic interaction between AVPR1b and CRHR1 genes in susceptibility to MDD (P=0.017). Polymorphisms of CRHR1 and AVPR1b may modify susceptibility to mood disorders.

Mice Genetically Deficient in Vasopressin V1a and V1b Receptors Are Resistant to Jet Lag

Jet-lag symptoms arise from temporal misalignment between the internal circadian clock and external solar time. We found that circadian rhythms of behavior (locomotor activity), clock gene expression, and body temperature immediately reentrained to phase-shifted light-dark cycles in mice lacking vasopressin receptors V1a and V1b (V1a(-/-)V1b(-/-)). Nevertheless, the behavior of V1a(-/-)V1b(-/-) mice was still coupled to the internal clock, which oscillated normally under standard conditions. Experiments with suprachiasmatic nucleus (SCN) slices in culture suggested that interneuronal communication mediated by V1a and V1b confers on the SCN an intrinsic resistance to external perturbation. Pharmacological blockade of V1a and V1b in the SCN of wild-type mice resulted in accelerated recovery from jet lag, which highlights the potential of vasopressin signaling as a therapeutic target for management of circadian rhythm misalignment, such as jet lag and shift work.

Pharmacological characterization of FE 201874, the first selective high affinity rat V1A vasopressin receptor agonist

Distinct vasopressin receptors are involved in different physiological and behavioural functions. Presently, no selective agonist is available to specifically elucidate the functional roles of the V1A receptor in the rat, one of the most widely used animal models. FE 201874 is a new derivative of the human selective V1A receptor agonist F180. In this study, we performed a multi-approach pharmacological and functional characterization of FE 201874 to determine whether it is selective for V1A receptors. We modified an available human selective V1A receptor agonist (F180) and determined its pharmacological properties in cell lines expressing vasopressin/oxytocin receptors (affinity and coupling to second messenger cascades), in an ex vivo model (aorta ring contraction) and in vivo in rats (proliferation of adrenal cortex glomerulosa cells and lactation). FE 201874 exhibited nanomolar affinity for the rat V1A receptor; it was highly selective towards the rat V1B and V2 vasopressin receptors and behaved as a full V1A agonist in all the pharmacological tests performed. FE 201874 bound to the oxytocin receptor, but with moderate affinity, and behaved as an oxytocin antagonist in vitro, but not in vivo. On functional grounds, all the data demonstrate that FE 201874 is the first selective agonist of the rat V1A receptor isoform available. Hence, FE 201874 may have potential as a treatment for the vasodilator-induced hypotension occurring in conditions such as septic shock and could be the most suitable compound for discriminating between the behavioural effects of arginine vasopressin and oxytocin.

Association between OPCRIT dimensions and polymorphisms of HPA axis genes in bipolar disorder

The aim of the study was to investigate the possible association between polymorphisms of HPA axis genes-CRHR1 (corticotrophin-releasing hormone receptor), NR3C1 (glucocorticoid receptor) and AVPR1B (arginine vasopressin receptor) and dimensions of bipolar disorder assessed by OPCRIT.We examined 560 patients with diagnosis of bipolar disorder (n=457) and unipolar disorder (n=103). Diagnosis was established by SCID and OPCRIT.We found association between polymorphisms of AVPR1b gene and psychotic dimension and CRHR1 polymorphisms and excitement and psychotic dimension.Our results suggest possible involvement of the AVPR1b and CRHR1 genes in the ethiology of psychotic features in the course of affective disorders, and possible involvement of CRHR1 gene in the ethiology of bipolar disorder.

Identification of Small-Molecule Agonists of Human Relaxin Family Receptor 1 (RXFP1) by Using a Homogenous Cell-Based cAMP Assay

The relaxin hormone is involved in a variety of biological functions, including female reproduction and parturition, as well as regulation of cardiovascular, renal, pulmonary, and hepatic functions. It regulates extracellular matrix remodeling, cell invasiveness, proliferation, differentiation, and overall tissue homeostasis. The G protein–coupled receptor (GPCR) relaxin family receptor 1 (RXFP1) is a cognate relaxin receptor that mainly signals through cyclic AMP second messenger. Although agonists of the receptor could have a wide range of pharmacologic utility, until now there have been no reported small-molecule agonists for relaxin receptors. Here, we report the development of a quantitative high-throughput platform for an RXFP1 agonist screen based on homogenous cell-based HTRF cyclic AMP (cAMP) assay technology. Two small molecules of similar structure were independently identified from a screen of more than 365 677 compounds. Neither compound showed activity in a counterscreen with HEK293T cells transfected with an unrelated GPCR vasopressin 1b receptor. These small-molecule agonists also demonstrated selectivity against the RXFP2 receptor, providing a basis for future medicinal chemistry optimization of selective relaxin receptor agonists.

Evidence for involvement of central vasopressin V1b and V2 receptors in stress‐induced baroreflex desensitization

It is well recognized that vasopressin modulates the neurogenic control of the circulation. Here, we report the central mechanisms by which vasopressin modulates cardiovascular response to stress induced by immobilization. Experiments were performed in conscious male Wistar rats equipped with radiotelemetric device for continuous measurement of haemodynamic parameters: systolic and diastolic BP and heart rate (HR). The functioning of the spontaneous baro-receptor reflex (BRR) was evaluated using the sequence method and the following parameters were evaluated: BRR sensitivity (BRS) and BRR effectiveness index (BEI). Under baseline physiological conditions intracerebroventricular injection of 100 and 500 ng of selective non-peptide V1a or V1b or V2 receptor antagonist did not modify BP, HR and BRR. Rats exposed to 15 min long stress by immobilization exhibited increase of BP, HR, reduction of BRS and no change in BEI. Pretreatment of rats with V1a receptor antagonist did not modulate the BP, HR, BRS and BEI response to stress. Pretreatment of rats with V1b receptor and V2 receptor antagonist, at both doses, prevented BRR desensitization and tachycardia, but failed to modulate stress-induced hypertension. Vasopressin by the stimulation of central V1b- and V2-like receptors mediates stress-induced tachycardia and BRR desensitization. If these mechanisms are involved, BRR desensitization in heart failure and hypertension associated with poor outcome, they could be considered as novel targets for cardiovascular drug development.

Neurocardiovascular Effects of V1b Receptor Blockade within Paraventricular Nucleus in Conscious Sprague Dawley Rats

The paraventricular nucleus (PVN) plays a critical role in both renal sympathetic nerve activity (RSNA) and vasopressin (AVP) secretion by the neurohypophysis. AVP is also released from dendrites of magnocellular neurons within PVN. In addition to V1a receptors, data indicate V1b receptors are present on PVN neurons. We tested the hypothesis that inhibition of V1b receptors within the PVN inhibits increases in mean arterial pressure (MAP) and RSNA induced by AVP injection into PVN. Male Sprague Dawley rats were instrumented. Studies were performed in awake unrestrained rats at least 24 hr after recovery from anesthesia. Baseline MAP, heart rate or RSNA did not differ among the groups. Microinjection of 100 ng AVP into the PVN increased MAP from 138.2 ± 3.1 (baseline) to 151.0 ± 3.2 mmHg (10 min, P<0.01). RSNA increased 47 ± 6.6%baseline (P<0.01). Pre‐injection with 100 ng of the V1b blocker nelivaptan significantly inhibited the pressor, tachycardic and RSNA responses (P<0.05 vs control). Experiments performed after ganglionic blockade with chlorisodamine indicate that the pressor response to central AVP is also in part due to an increase in plasma AVP. Vehicle did not block any of the responses. These findings support the concept that V1b receptors within PVN may be activated by dendritic release of AVP that stimulates both RSNA and peripheral release of AVP.

Vasopressin: a novel target for the prevention and retardation of kidney disease?

After several decades during which little attention was paid to vasopressin and/or urine concentration in clinical practice, interest in vasopressin has renewed with the availability of new, potent, orally active vasopressin-receptor antagonists--the vaptans--and with the results of epidemiological studies evaluating copeptin (a surrogate marker of vasopressin) in large population-based cohorts. Several experimental studies in rats and mice had previously shown that vasopressin, acting via vasopressin V2 antidiuretic receptors, contributes to the progression of chronic kidney disease; in particular, to autosomal dominant polycystic kidney disease. New epidemiological studies now suggest a role for vasopressin in the pathogenesis of diabetes mellitus and metabolic disorders via activation of hepatic V1a and/or pancreatic islet V1b receptors. The first part of this Review describes the adverse effects of vasopressin, as revealed by clinical and experimental studies in kidney diseases, hypertension, diabetes and the metabolic syndrome. The second part provides insights into vasopressin physiology and pathophysiology that may be relevant to the understanding of these adverse effects and that are linked to the excretion of concentrated nitrogen wastes and associated hyperfiltration. Collectively, the studies reviewed here suggest that more attention should be given to the vasopressin-thirst-urine concentration axis in clinical investigations and in patient care. Whether selective blockade of the different vasopressin receptors may provide therapeutic benefits beyond their present indication in hyponatraemia requires new clinical trials.

Family-Based Study of AVPR1B Association and Interaction with Stressful Life Events on Depression and Anxiety in Suicide Attempts

The cortisol response to psychosocial stress may become dysregulated in stress-related disorders. It is potentiated by pituitary secretion of adrenocorticotropic hormone (ACTH), which is, in part, regulated by arginine vasopressin receptor-1B (AVPR1B). AVPR1B variants were previously reported to associate with mood and anxiety disorders. This study aims, for the first time, to investigate association of AVPR1B genetic variants with mood and anxiety outcomes in suicidal behavior.Using a family-based study design of 660 complete nuclear family trios with offspring who have made a suicide attempt (SA), we tested the direct association and linkage of AVPR1B single nucleotide polymorphisms (SNPs) with SA, as well as with depression and anxiety in SA. Main findings were the association and linkage of AVPR1B exon 1 SNP rs33990840 and a major 6-SNP haplotype representative of all common AVPR1B-SNPs, on the outcome of high Beck Depression Inventory scores in SA. By contrast, genetic associations with lifetime diagnoses of depression and anxiety in SA or gene-environment interactions between AVPR1B variants and stressful life events (SLEs) were not significant. An exploratory screen of interactions between AVPR1B and CRHR1 (corticotropin-releasing hormone receptor-1), the principal pituitary regulator of ACTH secretion, showed no support for gene-gene interactions on the studied outcomes. The results suggest that AVPR1B genetic variation, eg, non-synonymous SNP rs33990840 mediating putative consequences on ligand binding, has a role in SA etiology characterized by elevated depression symptoms, without involving AVPR1B-moderation of SLEs.

Vasopressin depresses long term potentiation in the mouse hippocampus.

Event Abstract Back to Event Vasopressin depresses long term potentiation in the mouse hippocampus. Magda Chafai1, Gilles Guillon1 and Michel G. Desarmenien1* 1 Centre National de la Recherche Scientifique, France Vasopressin, besides its well known endocrine actions, is now recognized as a neurotransmitter in the brain, implicated in the regulation of social and affective behavior. Several recent findings indicate an involvement of the V1a and V1b vasopressin receptors in stress and depression and point out the limbic system as a putative target. The V1a receptor has a wide distribution but the V1b receptor displays a particularly high expression in the CA2 pyramidal area of the hippocampus. Accordingly, we have focused on this region to determine the effect of vasopressin on synaptic activity. Either whole-cell recording from the soma of pyramidal CA2 neurons or field recording along their dendrites in acute slices from C57Bl6 mice were performed. The synaptic activity in response to stimulation of the LIII entorhinal cortex (EC) afferents was measured. High frequency stimulation (HFS) induced a long term potentiation (LTP) of the excitatory post synaptic potential (EPSP) in the majority of pyramidal cells. Bath application of vasopressin (1 min., 10-100 nM) transiently decreased the LTP-enhanced EPSP by 15%. Of interest is the fact that the vasopressin-induced EPSP reduction was observed only after LTP establishment. In addition, vasopressin had no effect on the EPSP recorded in CA1 pyramidal cells in response to stimulation of the Schaffer collaterals, even after establishment of a stable LTP. Our data indicate that vasopressin, by decreasing specifically a synaptic input on CA2 pyramidal cells after LTP, can modulate the recently described (Chevaleyre and Siegelbaum, Neuron, 2010) disynaptic pathway involving EC afferents, the CA2 pyramidal cells and their target CA1 neurons. The identity of the vasopressin receptors implicated in this response, and the cognitive consequences of this inhibition, will be the matter of our future studies. Acknowledgements C.M. supported by ANR. Keywords: vasopressin, LTP, Stress, Physiological, CA2 Region, Hippocampal, Memory Conference: 4th Conference of the Mediterrarnean Neuroscience Society, Istanbul, Turkey, 30 Sep - 3 Oct, 2012. Presentation Type: Symposium Topic: Abstracts Citation: Chafai M, Guillon G and Desarmenien MG (2013). Vasopressin depresses long term potentiation in the mouse hippocampus.. Conference Abstract: 4th Conference of the Mediterrarnean Neuroscience Society. doi: 10.3389/conf.fnhum.2013.210.00014 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 29 Jan 2013; Published Online: 11 Apr 2013. * Correspondence: Dr. Michel G Desarmenien, Centre National de la Recherche Scientifique, Montpellier, France, mdesarmenien@igf.cnrs.fr Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Magda Chafai Gilles Guillon Michel G Desarmenien Google Magda Chafai Gilles Guillon Michel G Desarmenien Google Scholar Magda Chafai Gilles Guillon Michel G Desarmenien PubMed Magda Chafai Gilles Guillon Michel G Desarmenien Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

The effect of vasopressin 1b receptors (V1bRs) blockade on the HPA axis activity in rats exposed to acute heat stress

Thermal stressors such as low and high ambient temperature elicit an abundance of neuroendocrine responses including activation of the hypothalamo-pituitary-adrenal (HPA) axis and arginine vasopressin (AVP) release. The exposure to heat is a particularly interesting model for studying AVP action because this kind of stressor represents not only an unpleasant experience but also a threat to osmotic homeostasis. As AVP has long been recognized as a hormone involved in the modulation of HPA axis activity, the aim of this study was to elucidate the role of AVP in acutely heat-exposed rats using Nelivaptan, a selective vasopressin 1b receptor (V1bR) antagonist. Rats were exposed to high ambient temperature (38°C) for 60 min. The circulating hormones were determined by ELISA or chemiluminescence, and intrapituitary adrenocorticotropic hormone (ACTH) and V1bR level were determined by western blot. The results obtained show that V1bR blockade negatively affected the increase in blood ACTH caused by heat exposure. This treatment alone, or in combination with Nelivaptan, decreased intrapituitary V1bR levels while circulating AVP concentration was increased under the same conditions. Furthermore, a strong correlation was observed between blood ACTH and corticosterone concentration. In conclusion, our results directly confirm the positive role of AVP in the regulation of ACTH secretion from the pituitary in animals exposed to heat. Moreover, the results suggest that AVP from the general circulation influences pituitary V1bR.

Association, Haplotype, and Gene‐Gene Interactions of the HPA Axis Genes with Suicidal Behaviour in Affective Disorders

Family twin and adoption studies have noted the heritability of specific biological factors that influence suicidal behaviour. Exposure to stress is one of the factors that strongly contribute to suicide attempts. The biological response to stress involves the hypothalamic-pituitary-adrenal axis (HPA). Therefore, we found it interesting to study polymorphisms of genes involved in the HPA axis (CRHR1, NR3C1, and AVPBR1). The study was performed on 597 patients, 225 of whom had a history of suicide attempts. We did not observe any significant differences in the studied polymorphisms between the group of patients with a history of suicide attempts and the control subjects. Our haplotype analysis of the AVPR1b gene revealed an association between the GCA haplotype and suicide attempts; however, this association was not significant after correcting for multiple testing. We did not observe any other association in haplotype and MDR analysis. We report here a comprehensive analysis of the HPA axis genes and a lack of association for genetic variations regarding the risk of suicide attempts in affective disorder patients. Nonetheless, the inconsistencies with the previously published results indicate the importance of the further investigation of these polymorphisms with respect to the risk of suicide attempts.

Synaptic innervation to rat hippocampus by vasopressin-immuno-positive fibres from the hypothalamic supraoptic and paraventricular nuclei

The neuropeptide arginine vasopressin (AVP) exerts a modulatory role on hippocampal excitability through vasopressin V1A and V1B receptors. However, the origin and mode of termination of the AVP innervation of the hippocampus remain unknown. We have used light and electron microscopy to trace the origin, distribution and synaptic relationships of AVP-immuno-positive fibres and nerve terminals in the rat hippocampus. Immuno-positive fibres were present in all areas (CA1–3, dentate gyrus) of the whole septo-temporal extent of the hippocampus; they had the highest density in the CA2 region, strongly increasing in density towards the ventral hippocampus. Two types of fibres were identified, both establishing synaptic junctions. Type A had large varicosities packed with immuno-positive large-granulated peptidergic vesicles and few small clear vesicles forming type I synaptic junctions with pyramidal neuron dendrites, dendritic spines and with axonal spines. Type B had smaller varicosities containing mostly small clear vesicles and only a few large-granulated vesicles and established type II synaptic junctions mainly with interneuron dendrites. The AVP-positive axons in stratum oriens appeared to follow and contact metabotropic glutamate receptor 1α (mGluR1α)-immuno-positive interneuron dendrites. Fluoro-Gold injection into the hippocampus revealed retrogradely labelled AVP-positive somata in hypothalamic supraoptic and paraventricular nuclei. Hypothalamo-hippocampal AVP-positive axons entered the hippocampus mostly through a ventral route, also innervating the amygdala and to a lesser extent through the dorsal fimbria fornix, in continuation of the septal AVP innervation. Thus, it appears the AVP-containing neurons of the magnocellular hypothalamic nuclei serve as important sources for hippocampal AVP innervation, although the AVP-expressing neurons located in amygdala and bed nucleus of the stria terminalis reported previously may also contribute.

No association between polymorphisms and haplotypes of the AVPR1b, CRHR1 and NR3C1 genes and depression with melancholic features in the course of bipolar disorder

The present study included 130 patients with melancholic depression in the course of bipolar disorder and 732 healthy controls. No association was found for alleles, genotypes, or haplotype analysis for NR3C1, AVPR1b, and CRHR1 genes and melancholic depression.