Factors affecting the excitability of neurons in the bed nucleus of the stria terminalis (BNST) can have a significant impact on both the physiological and psychological state of well being of an organism. Hence, maladaptive activity in BNST-dependent neural circuitry has been implicated in peripheral disorders such as irritable bowel syndrome, and hypertension;as well as central disorders such as anxiety, depression, P-I-SD, drug addiction and recidivism. A common feature of these disorders is that many, if not all, can be precipitated, or exacerbated, by stressful life events, and there is considerable co-morbidity of these disorders. Many stress-induced neuropsychiatric syndromes respond to treatment with antidepressant drugs that modify serotonergic neurotransmission by blocking the serotonin transporter (SERT) or serotonin (5-HT) receptors. However, little is known about the interaction between stress hormones, such as corticotropin releasing factor (CRF), and 5-HT. Significantly, stress stimuli that activate BNST neurons also activate serotonergic neurons in the dorsal raphe, which innervate the BNST. Thus, stress stimuli ma sequentially activate CRF receptors followed by 5-HT receptors within the BNST. Our recent in vitro studies have shown that white postsynaptic 5-HT receptor activation can both excite, and inhibit BNST output neurons, the predominant response is inhibition. Importantly, our pilot data suggests that 5-HT inhibition of BNST neurons is significantly enhanced by CRF, thus providing a unique mechanism for the normal cessation of BNST activation once the initial stress response has been elicited by CRF. After chronic stress, such mechanisms may begin to break down, resulting in a failure to turn off stress-induced activation of BNST neurons, thus precipitating chronic states of arousal, anxiety and maladaptive behavioral patterns. The following Aims will test the hypothesis that: Under normal conditions, local CRF receptor activation acts to facilitate the inhibitory response of BNST neurons to 5-HT release. After chronic stress, there is a disruption of the CRF receptor-mediated facilitation of the 5-HT response. SA#I. Characterization of the CRF-induced modulation of serotonin responses recorded from neurons in the anteriorlateral BNST in control, and acutely stressed, animals. SA.#2. Characterization of the CRF receptor subtype/s mediating CRF-induced modulation of serotonin responses in the anteriorlateral BNST. SA#3. Characterization of the 5-HT receptor subtype/s mediating CRF-induced shift of serotonin responses in the anteriorlateral BNST. SA#4. Characterization of the effects of chronic repeated stress on the response of anteriorlateral BNST neurons to CRF and 5-HT. These SAs represent the first comprehensive analysis of the interaction between two major stress-activated neurotransmitter systems in a critical component of the central stress circuit, and mav contribute to the develoDment of novel treatment strateaies for several stress-related disorders.
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