Vasopressin in the regulation of serotonin and anxiety

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DESCRIPTION (provided by applicant): Social interactions are an important part of life. During infancy and adolescence, our survival depends on other people, and then throughout life we live, work, and play together. Disorders that disrupt our social behavior have devastating consequences for individuals, families, and society at large. In particular, anxiety and mood disorders can have devastating effects on social behavior and conversely can be impacted by our social interactions, and these disorders have a very high lifetime incidence (as high as 1 in 5). Over the last two decades, a number of pharmacological and gene-manipulation studies in rodents have implicated the neuropeptide vasopressin (AVP) in social behaviors including social memory, parental behavior, mating behavior, and pair-bonding. More recent evidence in mice suggests that deleting specific AVP receptors also alters anxiety. Anatomical evidence suggests that AVP neurons in the bed nucleus of the stria terminalis project to the dorsal raphe, where most of the forebrain's serotonin (5-HT) is produced. The 5-HT system has been an effective target for pharmacological treatment of anxiety and depression, specifically with the advent of selective 5-HT reuptake inhibitors (SSRIs). Based on the anatomical link between AVP and 5-HT, it was hypothesized that AVP would act on 5-HT neurons. Using whole cell voltage clamp electrophysiology, it was found that application of AVP caused an increase in the frequency of post synaptic currents (PSC)s in 5-HT neurons. This proposal aims to 1) determine whether the AVP mediated effects are due to actions on GABA or glutamate neurons using whole cell voltage clamp recordings of isolated PSCs in conjunction with glutamate or GABA receptor antagonists and by using immunohistochemistry for AVP and markers of glutamate and GABA neurons; 2) determine which AVP receptor is responsible for the observed effects using whole cell voltage clamp recording in conjunction with application of antagonists selective for different AVP receptor subtypes to isolate the relevant receptor; and 3) identify the behavioral relevance of AVP action in the dorsal raphe. Because affiliative behaviors such as mating as opposed to antagonistic behaviors such as inter-male aggression are known to activate AVP cells in the BNST, animals will be exposed to these respective stimuli and their subsequent anxiety-related behavior will be measured in the elevated plus maze. Subsequently, if the predicted decrease in anxiety-related behavior in response to affiliative social stimuli is observed, then AVP antagonists will be administered into the dorsal raphe to try to block this effect in subsequent tests. The impact of these studies will be to 1) characterize the effect of AVP on 5-HT neurons, 2) increase our understanding of local circuitry within the dorsal raphe, 3) define pathways sensitive to social stimuli that alter 5-HT neuron activity, and 4) determine how positive and negative social interactions influence anxiety at a cellular and behavioral level.