Evidence has accumulated that postsynaptic serotonin (5-HT) receptors are an important site of action for hallucinogenic drugs. Concomitantly, there has been intensive study of 5-HT binding sites in brain and periphery. These sites have been classified into three main groups, most commonly referred to as 5-HT 1, 2 and 3. The 5-HT 1 sites have been further subdivided into 5-HT 1A, 1B, 1C and 1D. The overall goal of the present proposal is to characterize the electrophsiological actions of hallucinogens and related drugs mediated by 5-HT receptors postsynaptic to serotonergic raphe neurons. Hallucinogens to be tested include the ergot D-LSD, the indoles psilocin and N,N-dimeth-yltryptamine, and the phenylalkylamines mescaline and 2,5-dimethoxy-4-methylamphetamine. Their actions will be compared with those of presumably non-hallucinogenic agents including 5-HT, 5-carboxyamidotryptamine, lisuride, and 2-bromolysergic acid diethylamide. Modulation of excitatory actions of 5-HT by hallucinogens will also be investigated. Electrophysiological experiments (field potential recordings and both intracellular and extracellular unit studies) will be performed on the rat hippocampal slice in vitro. The actions of hallucinogens will be characterized in hippocampal field CA 1 and their electrophsiological effects compared with their potency and efficacy on the two 5-HT receptors linked to adenylate cyclase in membranes form rat hippocampus. The inhibition of adenylate cyclase will be assessed. LSD binds to all 5-HT 1 and 5-HT 2 sites. Regions of the hippocampal formation exhibiting the highest densities for 5-HT 1B, 5-HT 1C and 5-HT 2 sites will be examined to determine whether electophysiological effects can be linked to drug action at these sites. The possible linkage of the 5-HT 1B site to adenylate cyclase will be investigated. These studies should yield information on some serotonergic mechanisms of action of hallucinogens in the hippocampus and on the receptors and effectors through which their effects are mediated.
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