Inhibition of compulsive behavior by dextromethorphan on schedule-induced polydipsia in rats: Role of NMDA, sigma-1, and 5-HT receptors.
Pharmacology, biochemistry, and behavior May 29, 2026 Madeline T Van Fossen, Alexia G Dalton, Adam J Prus
Dextromethorphan, an FDA-approved drug for major depressive disorder when combined with bupropion, acutely reduces compulsive-like drinking in a rat model of obsessive-compulsive disorder. The drug acts as an inhibitor of serotonin transporters and an antagonist of sigma-1 and NMDA receptors. In the study, rats were trained in a schedule-induced polydipsia procedure, which models compulsive behavior, and were divided into low and high drinkers. Dextromethorphan dose-dependently decreased water consumption in both groups, while the NMDA receptor antagonist ketamine selectively reduced drinking only in high drinkers. However, none of the tested antagonists reversed dextromethorphan's effects, suggesting further investigation into its potential as an OCD treatment.