Hallucinogen-like actions of 5-methoxy-N,N-diisopropyltryptamine in mice and rats.

5-MeO-DIPT, a hallucinogenic drug similar to DMT, produced head-twitch responses in mice, an effect blocked by a serotonin 2A receptor antagonist. In rats trained to recognize LSD, 5-MeO-DIPT partially substituted for LSD (75% generalization) and suppressed response rates in a dose-dependent way; this effect was abolished by a 5-HT2A antagonist but not by a 5-HT1A antagonist. The drug showed micromolar affinity for 5-HT2A and 5-HT2C receptors and much higher affinity for 5-HT1A receptors in rat brain tissue. The results indicate that the 5-HT2A receptor is a key site of action for 5-MeO-DIPT, despite its in vitro selectivity for the 5-HT1A receptor.

Study at a glance

Abstract

Few studies have examined the effects of 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) in vivo. In these studies, 5-MeO-DIPT was tested in a drug-elicited head twitch assay in mice where it was compared to the structurally similar hallucinogen N,N-dimethyltryptamine (N,N-DMT) and challenged with the selective serotonin (5-HT)2A antagonist M100907, and in a lysergic acid diethylamide (LSD) discrimination assay in rats where its subjective effects were challenged with M100907 or the 5-HT 1A selective antagonist WAY-100635. Finally, the affinity of 5-MeO-DIPT for three distinct 5-HT receptors was determined in rat brain. 5-MeO-DIPT, but not N,N-DMT, induced the head twitch responses in the mouse, and this effect was potently antagonized by prior administration of M100907. In rats trained with LSD as a discriminative stimulus, there was an intermediate degree (75%) of generalization to 5-MeO-DIPT and a dose-dependent suppression of response rates. These interoceptive effects were abolished by M100907, but were not significantly attenuated by WAY-100635. Finally, 5-MeO-DIPT had micromolar affinity for 5-HT 2A and 5-HT 2C receptors, but much higher affinity for 5-HT 1A receptors. 5-MeO-DIPT is thus effective in two rodent models of 5-HT2 agonist activity, and has affinity at receptors relevant to hallucinogen effects. The effectiveness with which M100907 antagonizes the behavioral actions of this compound, coupled with the lack of significant antagonist effects of WAY-100635, strongly suggests that the 5-HT 2A receptor is an important site of action for 5-MeO-DIPT, despite its apparent in vitro selectivity for the 5-HT 1A receptor.