This proposal involves the application of modern molecular pharmacological techniques to a reanalysis of the direct effects of hallucinogens on central 5HT receptor subtypes (5HT-1a, 5HT- 1c and 5HT-2) and the adaptive changes which occur in these receptor systems with chronic administration of hallucinogens. The studies will focus on the transmembrane signaling pathways (phosphoinositide hydrolysis and adenylate cyclase) that link these receptors to intracellular sites of action in the rat central nervous system. The specific hypotheses are (1) that the correlation between hallucinogenic activity in humans and actions at 5HT receptors will be improved by considering efficacy (which reflects the ability of a given ligand/receptor complex to initiate a response) as well as potency (i.e., affinity) and (2) that adaptive regulation of central 5HT receptors following chronic administration of the hallucinogens will involve a more rapid and more profound desensitization of the receptor than loss of binding sites. Previous studies have shown that the 5HT-2 receptor in cerebral cortex and the 5HT-1c receptor which is highly localized in the choroid plexus are positively coupled to phospholipase C/phosphoinositide hydrolysis. On the other hand, the 5HT-1a site or a similar site is coupled to adenylate cyclase apparently both in a positive and a negative manner; i.e., 5HT activates adenylate cyclase in control preparations, but inhibits this enzyme if it is previously activated by forskolin and the pharmacological properties of the receptors mediating these effects are similar to the 5HT-1a site. The potency and efficacy of indoleamine and phenylethylamine hallucinogens in activating these transmembrane signaling pathways will be determined in rat brain preparations and compared with their potency in eliciting hallucinations in humans. Since tolerance occurs rapidly in man to the hallucinogenic actions of LSD-25 and othe hallucinogens, the effects of repeated administration of these drugs will be examined in rats in radioligand binding assays of the three receptor subtypes and in functional assays of the transmembrane signaling pathways. These studies will provide a complete picture of the action of hallucinogens at central 5HT receptors and perhaps shed light on the role of 5HT in the hallucinogenic effects of these drugs.
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