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      The vasopressin Avprlb receptor: Molecular and pharmacological studies

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          The distribution, pharmacology and function of the arginine vasopressin (Avp) lb receptor subtype (Avprlb) has proved more challenging to investigate compared to other members of the Avp receptor family. Avp is increasingly recognised as an important modulator of the hypothalamic–pituitary–adrenal (HPA) axis, an action mediated by the Avprlb present on anterior pituitary corticotrophs. The Avprlb is also expressed in some peripheral tissues including pancreas and adrenal, and in the hippocampus (HIP), paraventricular nucleus and olfactory bulb of the rodent brain where its function is unknown. The central distribution of Avprlbs is far more restricted than that of the Avprla, the main Avp receptor subtype found in the brain. Whether Avprlb expression in rodent tissues is dependent on differences in the length of microsatellite dinucleotide repeats present in the 5′ promoter region of the Avprlb gene remains to be determined. One difficulty of functional studies on the Avprlb, especially its involvement in the HPA axis response to stress, which prompted the generation of Avprlb knockout (KO) mouse models, was the shortage of commercially available Avprlb ligands, particularly antagonists. Research on mice lacking functional Avprlbs has highlighted behavioural deficits in social memory and aggression. The Avprlb KO also appears to be an excellent model to study the contribution of the Avprlb in the HPA axis response to acute and perhaps some chronic (repeated) stressors where corticotrophin-releasing hormone and other genes involved in the HPA axis response to stress do not appear to compensate for the loss of the Avprlb.

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          Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo–pituitary–adrenocortical responsiveness

          Appropriate regulatory control of the hypothalamo-pituitary-adrenocortical stress axis is essential to health and survival. The following review documents the principle extrinsic and intrinsic mechanisms responsible for regulating stress-responsive CRH neurons of the hypothalamic paraventricular nucleus, which summate excitatory and inhibitory inputs into a net secretory signal at the pituitary gland. Regions that directly innervate these neurons are primed to relay sensory information, including visceral afferents, nociceptors and circumventricular organs, thereby promoting 'reactive' corticosteroid responses to emergent homeostatic challenges. Indirect inputs from the limbic-associated structures are capable of activating these same cells in the absence of frank physiological challenges; such 'anticipatory' signals regulate glucocorticoid release under conditions in which physical challenges may be predicted, either by innate programs or conditioned stimuli. Importantly, 'anticipatory' circuits are integrated with neural pathways subserving 'reactive' responses at multiple levels. The resultant hierarchical organization of stress-responsive neurocircuitries is capable of comparing information from multiple limbic sources with internally generated and peripherally sensed information, thereby tuning the relative activity of the adrenal cortex. Imbalances among these limbic pathways and homeostatic sensors are likely to underlie hypothalamo-pituitary-adrenocortical dysfunction associated with numerous disease processes.
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            Microsatellite instability generates diversity in brain and sociobehavioral traits.

            Repetitive microsatellites mutate at relatively high rates and may contribute to the rapid evolution of species-typical traits. We show that individual alleles of a repetitive polymorphic microsatellite in the 5' region of the prairie vole vasopressin 1a receptor (avpr1a) gene modify gene expression in vitro. In vivo, we observe that this regulatory polymorphism predicts both individual differences in receptor distribution patterns and socio-behavioral traits. These data suggest that individual differences in gene expression patterns may be conferred via polymorphic microsatellites in the cis-regulatory regions of genes and may contribute to normal variation in behavioral traits.
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              Neuroendocrine pharmacology of stress.

              Exposure to hostile conditions initiates responses organized to enhance the probability of survival. These coordinated responses, known as stress responses, are composed of alterations in behavior, autonomic function and the secretion of multiple hormones. The activation of the renin-angiotensin system and the hypothalamic-pituitary-adrenocortical axis plays a pivotal role in the stress response. Neuroendocrine components activated by stressors include the increased secretion of epinephrine and norepinephrine from the sympathetic nervous system and adrenal medulla, the release of corticotropin-releasing factor (CRF) and vasopressin from parvicellular neurons into the portal circulation, and seconds later, the secretion of pituitary adrenocorticotropin (ACTH), leading to secretion of glucocorticoids by the adrenal gland. Corticotropin-releasing factor coordinates the endocrine, autonomic, behavioral and immune responses to stress and also acts as a neurotransmitter or neuromodulator in the amygdala, dorsal raphe nucleus, hippocampus and locus coeruleus, to integrate brain multi-system responses to stress. This review discussed the role of classical mediators of the stress response, such as corticotropin-releasing factor, vasopressin, serotonin (5-hydroxytryptamine or 5-HT) and catecholamines. Also discussed are the roles of other neuropeptides/neuromodulators involved in the stress response that have previously received little attention, such as substance P, vasoactive intestinal polypeptide, neuropeptide Y and cholecystokinin. Anxiolytic drugs of the benzodiazepine class and other drugs that affect catecholamine, GABA(A), histamine and serotonin receptors have been used to attenuate the neuroendocrine response to stressors. The neuroendocrine information for these drugs is still incomplete; however, they are a new class of potential antidepressant and anxiolytic drugs that offer new therapeutic approaches to treating anxiety disorders. The studies described in this review suggest that multiple brain mechanisms are responsible for the regulation of each hormone and that not all hormones are regulated by the same neural circuits. In particular, the renin-angiotensin system seems to be regulated by different brain mechanisms than the hypothalamic-pituitary-adrenal system. This could be an important survival mechanism to ensure that dysfunction of one neurotransmitter system will not endanger the appropriate secretion of hormones during exposure to adverse conditions. The measurement of several hormones to examine the mechanisms underlying the stress response and the effects of drugs and lesions on these responses can provide insight into the nature and location of brain circuits and neurotransmitter receptors involved in anxiety and stress.

                Author and article information

                Stress (Amsterdam, Netherlands)
                Informa Healthcare
                January 2011
                10 September 2010
                : 14
                : 1
                : 98-115
                [1 ]Henry Wellcome LINE, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, UK
                [2 ]Section on Neural Gene Expression, Department of Health and Human Services, National Institute of Mental Health, National Institutes of Health, Bethesda, MA 20892-4483, USA
                Author notes
                Correspondence: S. J. Lolait, Henry Wellcome LINE, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, UK. Tel: + 44 0117 331 3041. Fax: +44 0117 331 3035. E-mail: s.j.lolait@ 123456bristol.ac.uk
                © 2011 Informa Healthcare USA, Inc.

                This is an open access article distributed under the Supplemental Terms and Conditions for iOpenAccess articles published in Informa Healthcare journals , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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