Choroid plexus epithelial cells in primary culture: a model of 5HT1C receptor activation by hallucinogenic drugs.

Abstract

Behavioral, electrophysiological and biochemical evidence suggest that the 5HT2 receptor plays a role in the action of hallucinogenic agents. Considering the structural and functional similarities between the 5HT2 and 5HT1C receptors, we hypothesized that the 5HT1C receptor may also be an important site of action of hallucinogens. The present manuscript evaluates this hypothesis by examining the properties of hallucinogens in the phenalkylamine and indolealkylamine classes at 5HT1C receptors. Epithelial cells isolated from the rat choroid plexus have a high density of 5HT1C receptors linked to phosphoinositide hydrolysis. Comparison of the actions of drugs in cultured cells and whole choroid plexus confirmed that the cell culture system can serve as an in vitro model of 5HT1C receptor activation. 2,5-Dimethoxy-4-bromoamphetamine (DOB), 2,5-dimethoxy-4-methylamphetamine (DOM), 2,5-dimethoxy-4-iodoamphetamine (DOI) and 3,4-methylenedioxyamphetamine (MDA) were evaluated. The rank order of potency to activate 5HT1C receptors [(-)DOB greater than (+/-) DOI greater than (+)DOB greater than (-)DOM much greater than (-)MDA greater than (+) MDA] was consistent with the rank order of effective behavioral doses in rats and humans. The indolealkylamine hallucinogen, 5-methoxy-N,N-dimethyltryptamine was also a 5HT1C receptor agonist, as is the primary amine, 5-methoxytryptamine. These data, combined with previous studies showing that (+)LSD potently activates 5HT1C receptors, suggest that future investigations of the mechanism of action of hallucinogens should consider the role of 5HT1C receptors in addition to the more commonly investigated 5HT2 receptors.