Inhibition of Compulsive Behavior by Dextromethorphan on Schedule-Induced Polydipsia in Rats: Role of NMDA, Sigma-1, and 5-HT Receptors.

Dextromethorphan (DM) is an FDA-approved treatment for major depressive disorder when combined with bupropion. DM functions as an inhibitor for 5-HT membrane transporters and antagonist for sigma-1 receptors (S1Rs) and NMDA receptors, which are pharmacological actions potentially therapeutically relevant for obsessive-compulsive disorder (OCD). The present study examined DM and compounds selective for these receptor mechanisms using the schedule-induced polydipsia (SIP) procedure, a preclinical model of compulsive behavior. Rats were food-restricted and given a fixed-time 60-s schedule of food pellet delivery during experimental sessions. After 20 sessions, rats were ranked by water consumption and divided into low (LD) and high (HD) drinkers. DM, the 5-HT2A/C receptor agonist DOI, the S1R agonist SA4503, and noncompetitive NMDA receptor antagonist racemic ketamine were tested. Additionally, dose-combination tests assessed whether the 5-HT2A receptor antagonist M100907, the NMDA receptor agonist NMDA, or the S1R antagonist BD1047 reversed DM's effects. DM dose-dependently reduced water consumption in both LD and HD rats, and ketamine selectively reduced water intake in only HD rats. Both SA4503 and DOI reduced water consumption in the LD and HD rats. None of the antagonists reversed DM's suppression of SIP. These findings demonstrate that DM acutely reduces compulsive-like drinking in a SIP paradigm, suggesting further investigations into DM as a treatment for OCD.