Altered sensitivity of multiple brain serotonin (5HT) receptors has been hypothesized in the etiology and/or treatment of anxiety, depression, sleep disorders, sexual behaviors, and psychosis. The roles that the multiple 5HT receptor systems play in brain function are still largely unknown, as are the neuronal mechanisms through which 5HT receptors alter cellular function. To better understand the nature of the brain's 5HT receptors have been developed and will be used in conjunction with in vivo manipulations to further our understanding of the role these receptors systems play in brain function and the effects of drugs. a) Preliminary evidence for the existence of a novel brain 5HT receptor, the 5HT1D receptors, has been uncovered. Detailed radioligand binding and adenylate cyclase studies of the 5HT1D receptor will be performed in various mammalian tissues including rat and human brain. b) in order to determine the susceptibility of the 5-HT1D receptors system to sensitivity changes, 5HT transmission in rats will be altered by acute and chronic administration of serotonin neurotoxins, receptor antagonists, agonists, anxiolytics, antidepressants, and electroconvulsive shock. Alterations in the amount of 5-HT1D receptors, the interaction of the 5HT1D receptor with its associated GTP-binding protein, and the coupling between 5HT1D receptors and brain adenylate cyclase activity due to these perturbations will be monitored. c) Preliminary studies have demonstrated that 125I-DOI labels either alternatively, a unique 5HT2 receptor with high affinity for 5HT2 agonists or, alternatively, a unique 5HT2 receptor distinct from that labelled by 3H-ketanserin. In order to address this question the distribution and regulation of the 125I-DOI labelled receptors will be determined and compared with the distribution and regulation of 3H-ketanserin (an antagonist) labelled 5-HT2 receptors in multiple brain regions. d) In order to investigate the role of the brain 5HT1A receptor systems in the actions of antidepressants and novel anxiolytics the affects of these drugs on 3H-BMY 7378 (the first 5HT1A receptor antagonist radioligand), and on the associated 5HT1A receptor-mediated inhibition of adenylate cyclase activity will be monitored.
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