An Indoleamine Hallucinogen That Induces Stimulus Control Via 5-HT

WINTER, J. C., R. A. FILIPINK, D. TIMINERI, S. E. HELSLEY AND R. A. RABIN. The paradox of 5-methoxyN,N -dimethyltryptamine: An indoleamine hallucinogen that induces stimulus control via 5-HT 1 A receptors . PHARMACOL BIOCHEM BEHAV 65 (1) 75–82, 2000.—Stimulus control was established in rats trained to discriminate either 5-methoxyN,N -dimethyltryptamine (3 mg/kg) or ( 2 )-2,5-dimethoxy-4-methylamphetamine (0.56 mg/kg) from saline. Tests of antagonism of stimulus control were conducted using the 5-HT 1A antagonists ( 6 )-pindolol and WAY-100635, and the 5-HT 2 receptor antagonist pirenperone. In rats trained with 5-MeO-DMT, pindolol and WAY-100635 both produced a significant degree of antagonism of stimulus control, but pirenperone was much less effective. Likewise, the full generalization of 5-MeO-DMT to the selective 5-HT 1A agonist [ 6 ]-8-hydroxy-dipropylaminotetralin was blocked by WAY-100635, but unaffected by pirenperone. 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 ( 2 )-DOM, pirenperone completely blocked stimulus control, but WAY-100635 was inactive. The results obtained in rats trained with ( 2 )-DOM and tested with 5-MeO-DMT were more complex. Although the intraperitoneal route had been used for both training drugs, a significant degree of generalization of ( 2 )-DOM to 5-MeO-DMT was seen only when the latter drug was administered subcutaneously. Furthermore, when the previously effective dose of pirenperone was given in combination with 5-MeO-DMT (SC), complete suppression of responding resulted. However, the combination of pirenperone and WAY-100635 given prior to 5-MeO-DMT restored responding in ( 2 )-DOM-trained rats, and provided evidence of antagonism of the partial substitution of 5-MeO-DMT for ( 2 )-DOM. The present data indicate that 5-MeO-DMT–induced stimulus control is mediated primarily by interactions with 5-HT 1A receptors. In addition, however, the present findings suggest that 5-MeO-DMT induces a compound stimulus that includes an element mediated by interactions with a 5-HT 2 receptors. The latter component is not essential for 5-MeO-DMT–induced stimulus control, but is revealed in animals tested or trained with a 5-HT 2 -selective agonist such as ( 2 )-DOM. Based upon the present data, we conclude that 5-MeO-DMT differs from DOM with respect to the serotonergic element that mediates stimulus control in the rat, but that it shares with DOM a functionally significant interaction with 5-HT 2 receptors. © 1999 Elsevier Science Inc.