PSYCHOTROPIC DRUGS AND SEROTONIN RECEPTORS

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The purpose of this project is to determine the location and pharmacological sensitivity of different populations of putative serotonin (5-hydroxytryptamine, 5-HT) receptors in the central nervous system (CNS). To accomplish this the project is designed as an interdisciplinary program utilizing the technique for the autoradiographic localization of ligand-binding sites coupled with computer-assisted microdensitometry and image processing. Application of the ligand-binding technique to brain homogenates has resulted in the identification of at least two major populations of putative 5-HT receptors, the 5-HT1 and 5-HT2 receptors. In addition, we have demonstrated that the 5-HT1 sites, defined by the high-affinity binding of 3H-5-HT, actually represent a heterogeneous population of sites, and there are now data suggesting functional correlates of the subtypes of 5-HT1 sites. Results using the autoradiographic technique suggest that it can be used to provide a means of determining the precise distributions of these sites within very small areas of the brain. Such localization is possible because of the availability of drugs which can distinguish between the different types of 5-HT receptors. For example, the neuroleptic spiperone shows at least a 3000-fold difference in its affinities for two different populations of 3H-5-HT binding sites in the rat brain, and it is therefore possible to select a concentration of this drug which can inhibit the binding of 3H-5-HT to one site without affecting its binding to the other. Recently, we have also determined that other compounds, e.g., psilocybin and other indoleamines, can also discriminate between different types of 3H-5-HT sites. Thus, combining the autoradiographic technique with drugs which can discriminate between different types of 5-HT receptors should allow the localization of specific subtypes of putative serotonergic receptors within the CNS. Since serotonin has been implicated in a number of behaviors and disease states, including sleep, eating, perception of pain, depression and schizophrenia to name a few, it is hoped that the localization and characterization of different types of serotonergic receptors will aid in defining the roles and corresponding sites of action of this central neurotransmitter and ultimately lead to the development of new therapeutic agents.