Agonist activity of LSD and lisuride at cloned 5HT(2A) and 5HT(2C) receptors

Abstract

Evidence from studies with phenylisopropylamine hallucinogens indicates that the 5HT(2A) receptor is the likely target for the initiation of events leading to hallucinogenic activity associated with LSD and related drugs. Recently, lisuride (a purported non-hallucinogenic congener of LSD) was reported to be a potent antagonist at the 5HT(2C) receptor and an agonist at the 5HT(2A) receptor. LSD exhibited agonist activity at both receptors. These data were interpreted as indicating that the 5HT(2C) receptor might be the initiating site of action for hallucinogens. To test this hypothesis, recombinant cells expressing 5HT(2A) and 5HT(2C) receptors were used to determine the actions of LSD and lisuride. LSD and lisuride were potent partial agonists at 5HT(2A) receptors with EC50 values of 7.2 nM and 17 nM, respectively. Also, LSD and lisuride were partial agonists at 5HT(2C) receptors with EC50 values of 27 nM and 94 nM, respectively. We conclude that lisuride and LSD have similar actions at 5HT(2A) and 5HT(2C) receptors in recombinant cells. As agohist activity at brain 5HT(2A) receptors has been associated with hallucinogenic acitivity, these results indicate that lisuride may possess hallucinogenic activity, although the psychopharmacological effects of lisuride appear to be different from the hallucinogenic effects of LSD.