A multiphasic study serotonin (5HT) receptor/function relationships in the central nervous system (CNS) is proposed. Electrophysiological and radioligand binding studies have suggested the existence of more than one type of 5HT receptor in the CNS. In this proposal, extensive biochemical and behavioral studies are designed to obtain additional evidence for multiple CNS 5HT receptors. Using multiple ligands, the pharmacological characteristics and the mechanisms of regulation of the 5HT-related binding sites will be determined. A major effort will focus on the functional significance of the 5HT receptors defined in these in vitro radioligand binding studies. We will develop and characterized in vitro and in vivo biochemical models of brain 5HT receptor systems. Results of our earlier studies showed that terminal 5HT autoreceptors are pharamacologically similar to the 5HT1 binding site. In the current proposal, we plan to investigate further the possibility that the 5HT1 binding site may serve as the recognition site for 5HT autoreceptors and also for release-inhibiting 5HT receptors on the terminals of other neuronal systems. A number of in vivo behavioral models of 5HT receptor activation will also be characterized; these include the discriminative stimulus effects of 5HT agonists, the 5HT behavioral syndrome, and disruption of operant responding by 5HT agonists. Previous work suggests that these behaviors may be mediated by different subtypes of 5HT receptors. We will compare the relative potencies of the various 5HT antagonists in blocking these behaviors to their relative affinities at the 5HT binding sites for the purpose of identifying receptor/behavioral correlates of functional significance. Considering the possible role of 5HT in sleep, aggression, and the etiology of psychotic depression, the characterization of subtypes of 5HT receptors and drugs selective for these sites may have important implications for pharmacological intervention of mental illness.
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