Stimulus control by 5-methoxy-N,N-dimethyltryptamine in wild-type and CYP2D6-humanized mice.

In mice genetically modified to express human CYP2D6 (Tg-CYP2D6) and wild-type mice, the psychedelic 5-MeO-DMT produced similar rates of learning a drug discrimination task. Bufotenine did not substitute for 5-MeO-DMT, while its lipid-soluble analog acetylbufotenine produced intermediate substitution. Combining harmaline with 5-MeO-DMT significantly increased drug-appropriate responding in both mouse types, indicating harmaline enhances 5-MeO-DMT's stimulus effects. Harmaline alone also produced significant 5-MeO-DMT-appropriate responding in Tg-CYP2D6 mice, suggesting metabolic interactions. No differences between wild-type and Tg-CYP2D6 mice were found in acquisition or responses to bufotenine and acetylbufotenine.

Study at a glance

Abstract

In previous studies we have observed that, in comparison with wild type mice, Tg-CYP2D6 mice have increased serum levels of bufotenine [5-hydroxy-N,N-dimethyltryptamine] following the administration of 5-MeO-DMT. Furthermore, following the injection of 5-MeO-DMT, harmaline was observed to increase serum levels of bufotenine and 5-MeO-DMT in both wild-type and Tg-CYP2D6 mice. In the present investigation, 5-MeO-DMT-induced stimulus control was established in wild-type and Tg-CYP2D6 mice. The two groups did not differ in their rate of acquisition of stimulus control. When tested with bufotenine, no 5-MeO-DMT-appropriate responding was observed. In contrast, the more lipid soluble analog of bufotenine, acetylbufotenine, was followed by an intermediate level of responding. The combination of harmaline with 5-MeO-DMT yielded a statistically significant increase in 5-MeO-DMT-appropriate responding in Tg-CYP2D6 mice; a comparable increase occurred in wild-type mice. In addition, it was noted that harmaline alone was followed by a significant degree of 5-MeO-DMT-appropriate responding in Tg-CYP2D6 mice. It is concluded that wild-type and Tg-CYPD2D6 mice do not differ in terms of acquisition of stimulus control by 5-MeO-DMT or in their response to bufotenine and acetylbufotenine. In both groups of mice, harmaline was found to enhance the stimulus effects of 5-MeO-DMT.