The paradox of 5-methoxy-N,N-dimethyltryptamine: An indoleamine hallucinogen that induces stimulus control via 5-HT1A receptors

Stimulus control was established in rats trained to discriminate either 5-m ethoxy-N,N-dimethyltryptamine (3 mg/kg) or (-)-2,5-dimethoxy-4-methylamphet amine (0.56 mg/kg) from saline. Tests of antagonism of stimulus control wer e conducted using the 5-HT1A antagonists (+/-)-pindolol and WAY-100635, and the 5-HT2 receptor antagonist pirenperone. In rats trained with 5-MeO-DMT, pindolol and WAY-100635 both produced a significant degree of antagonism o f stimulus control, but pirenperone was much less effective. Likewise, the full generalization of 5-MeO-DMT to the selective 5-HT1A agonist [+/-]-8-hy droxy-dipropylaminotetralin was blocked by WAY-100635, but unaffected by pi renperone. In contrast, the partial generalization of 5-MeO-DMT to the 5-HT 2 agonist DOM was completely antagonized by pirenperone, but was unaffected by WAY-100635. Similarly, in rats trained with (-)-DOM, pirenperone comple tely blocked stimulus control, but WAY-100635 was inactive. The results obt ained in rats trained with (-)-DOM and tested with 5-MeO-DMT were more comp lex. Although the intraperitoneal route had been used for both training dru gs, a significant degree of generalization of (-)-DOM to 5-MeO-DMT was seen only when the latter drug was administered subcutaneously. Furthermore, wh en the previously effective dose of pirenperone was given in combination wi th 5-MeO-DMT (SC), complete suppression of responding resulted. However, th e combination of pirenperone and WAY-100635 given prior to 5-MeO-DMT restor ed responding in (-)-DOM-trained rats, and provided evidence of antagonism of the partial substitution of 5-MeO-DMT for (-)-DOM. The present data indi cate that 5-MeO-DMT-induced stimulus control is mediated primarily by inter actions with 5-HT1A receptors. In addition, however, the present findings s uggest that 5-MeO-DMT induces a compound stimulus that includes an element mediated by interactions with a 5-HT2 receptors. The latter component is no t essential for 5-MeO-DMT-induced stimulus control, but is revealed in anim als tested or trained with a 5-HT2-selective agonist such as (-)-DOM. Based upon the present data, we conclude that 5-MeO-DMT differs from DOM with re spect to the serotonergic element that mediates stimulus control in the rat , but that it shares with DOM a functionally significant interaction with 5 -HT2 receptors. (C) 1999 Elsevier Science Inc.