HALLUCINOGENS PHARMACOLOGY ON 5-HT RECEPTORS SUBTYPE

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The goal of this project is to understand similarities and differences between actions of hallucinogenic drugs of abuse and their non hallucinogen congeners on serotonin receptors and their effectors. Understanding of these molecular events is required for the development of rational therapeutic agents and may provide antidotes to these drug of abuse as well as for the general knowledge of the pharmacology of behavior-altering drugs. The underlying hypothesis of this project-- which is one component of a four IRPG proposal--is that hallucinogens are 5-HT (5-hydroxytryptamine; serotonin) agonists, with low efficacy and slow kinetics of receptor activation and desensitization. By contrast, the chemically related non-hallucinogens are either pure 5-HT antagonists or are 5-HT agonists with high efficacy and a fast kinetic of action. We propose to study actions of hallucinogens and structurally related non hallucinogens at two levels: i) drug-receptor interaction; and ii) specific cellular events distal to this interaction. Drug relative efficacy (RE) values will be determined on human 5-HT2 and 5-HT1C receptors transfected into clonal cell lines by two complementary approaches; functional and thermodynamic binding assays. Response parameters to compounds from three chemically distinct groups--ergolines, indolealkylamines and phenylalkylamines--will be determined by measuring various second messenger assay (production of inositol phosphates and diacylglycerol, increased [Ca2+]i, arachidonic acid release, amplification of adenylyl cyclase activity, choline accumulation and modulation of receptor-Gi linked inhibition of adenylyl cyclase). Thermodynamic binding parameters of drug receptor complex at different affinity states will be carried out as the second approach to assess RE values. These methods will be utilized by the pharmacological core that serves the other three projects in this IRPG. Interactions between cellular pathways activated by distinct 5-HT receptor subtypes ("receptor cross talk"), such as the attenuation 5-HT-1-beta-like by 5-HT1C, alters drug RE values on the former receptor. Also, activation of the 5-HT1C or the 5-HT2 receptor is associated with a rapid desensitization that appears to be dependent on drug RE values. To gain a detailed understanding of these intricate phenomena, we propose to study the pharmacological profile of a given drug by an integrated approach, where recognition and changes of affinity states of receptor-drug complex, kinetics of second messenger generation and of receptor modulation (desensitization) and receptor cross-talk are studies in a comparative manner with hallucinogens and structurally related non hallucinogens. Finally, due to the continuous discovery of novel 5-HT receptor subtype that may be important targets for hallucinogenic drugs of abuse, we propose to apply the same approach to a likely candidate, the 5-HT6 receptor.