The overall goal is to identify serotonin (5HT) receptor/function relationships in the central nervous system. Several functional responses will be examined with the aim of relating these responses to 5HT """"""""receptor"""""""" defined in radioligand binding assays. The actions of putative 5HT agonists and antagonists will be examined inan effort to develop a more precise classification of these drugs at each of the identified 5HT receptor subtypes. We have demonstrated that the 5HT-2 recognition site is linked to phosphoinositide hydrolysis in rat cerebral cortex. These studies will be extended to a determination of the second messenger products of 5HT-2 receptor activation and to evaluate the relationship between GTP sensitive agonist high affinity state and efficacy at the 5HT-2 receptor. Furthermore, the possibility that the phosphoinositide hydrolysis pathway functions as a transducing mechanism for the other 5HT receptors will be investigated. Behavioral models that reflect 5HT-2 receptor function and are bidirectional sensitive to increases and decreases in 5HT transmission will be developed. Another goal of this project is to define, both descriptively and mechanistically, the adaptive processes in central 5HT receptor systems after chronic manipulations of 5HT transmission. For each of the three major 5HT receptors (1a, 1b and 2), we plan to study the adaptive changes at the cellular/molecular level (the membrane recognition site and signaling pathways) and at level of the whole organism (by looking at the behavioral output of the brain). Frequently, functional (behavioral) alterations in 5HT receptor systems are not explained by changes in 5HT recognition sites measured by radioligand binding. We plan therefore to examine biochemical events which are coupled to the recognition sites to evaluate changes in signal transduction as a possible molecular mechanism of regulation in 5HT receptor systems. Furthermore, such multilevel analyses of adaptive responses to 5HT receptor systems will serve to test hypotheses concerning the relation of a specific biochemical response to a specific behavior as well as provide a framework for examining the role of 5HT in the therapeutic actions of drugs used in the treatment of mental diseases.
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