AGONIST PROPERTIES OF N,N-DIMETHYLTRYPTAMINE AT SEROTONIN 5-HT2A AND 5-HT2C RECEPTORS

Extensive behavioral and biochemical evidence suggests an agonist role at the 5-HT2A receptor, and perhaps the 5-HT2C receptor, in the mecha nism of action of hallucinogenic drugs. However the published in vitro pharmacological properties of N,N-dimethyltryptamine (DMT), an halluc inogenic tryptamine analog, are not consistent with this hypothesis. W e, therefore, undertook an extensive investigation into the properties of DMT at 5-HT2A and 5-HT2C receptors. In fibroblasts transfected wit h the 5-HT2A receptor or the 5-HT2C receptor, DMT activated the major intracellular signaling pathway (phosphoinositide hydrolysis) to an ex tent comparable to that produced by serotonin. Because drug efficacy c hanges with receptor density and cellular microenvironment, we also ex amined the properties of DMT in native preparations using a behavioral and biochemical approach. Rats were trained to discriminate an antago nist ketanserin from an agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-amino propane (DOI) in a two-lever choice paradigm. Pharmacological studies showed that responding on the DOI and ketanserin lever reflected agoni st and antagonist activity at 5-HT2A receptors, and hence, was a suita ble model for evaluating the in vivo functional properties of DMT, Lik e other 5-HT2A receptor agonists, DMT substituted fully for DOI. Intac t choroid plexus was used to evaluate the agonist properties at endoge nous 5-HT2C receptors; DMT was a partial agonist at 5-HT2C receptors i n this native preparation. Thus, we conclude that DMT behaves as an ag onist at both 5-HT2A and 5-HT2A receptors. One difference was evident in that the 5-HT2C, but not the 5-HT2A, receptor showed a profound des ensitization to DMT over time. This difference is interesting in light of the recent report that the hallucinogenic activity of DMT does not tolerate in humans and suggests the 5-HT2C receptor plays a less prom inent role in the action of DMT. (C) 1998 Elsevier Science Inc.