MECHANISMS AND REGULATION OF 5-HT RECEPTORS IN THE CNS

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During the past decade, especially after the introduction of in vitro binding techniques, considerable progress has been made in understanding the types of serotonin receptors present in the central nervous system. In spite of these advances, until recently, little was known about the electrophysiological actions mediated by these receptors in the brain and their underlying mechanisms. During the past few years, substantial advances have been made regarding the actions and mechanism of one of the receptors, the 5-HTlA receptor. Yet, very little is still known about the electrophysiological actions and mechanisms of the other 5-HT receptors in the brain and about the mechanisms controlling central serotonergic responsiveness. Therefore, this application proposes to examine these questions using intracellular recordings in vitro brain slices from the hippocampus and the anterior cingulate cortex, two areas enriched in different types of 5-HT binding sites. In a first series of experiments, advantage will be taken of previous knowledge and experience gained with 5-HTlA responses in the hippocampus to examine the mechanisms underlying the regulation of receptor sensitivity in this area and the actions of synaptically released 5-HT. Specifically, the role adenylate cyclase inhibition and inositol phospholipids play in the regulation of receptor sensitivity in this area will be determined, and the hypothesis that chronic antidepressant treatment might change 5-HT responsiveness by acting on 5-HT receptors coupled to inositol phospholipids will be tested. In addition, the role of the different 5-HT receptors present in hippocampus in mediating the effects of synaptically released 5-HT will be determined. Later, in a second series of experiments, the actions and mechanisms associated with other 5-HT receptors will be examined by recording in the anterior cingulate cortex to identify and characterize the actions mediated by the 5-HT2 and 5-HT1C receptors present in this area and to determine their ionic and molecular mechanisms of action. It is expected that these studies will significantly contribute to our understanding of the actions of 5-HT in the brain and the molecular pharmacology of central 5-HT receptors. In addition, it is also hoped that these basic studies will contributed to a better understanding of receptor regulation in general and the prefrontal cortex in particular and will suggest new therapeutic approaches for the treatment of mental diseases.