Inhibition of compulsive behavior by dextromethorphan on schedule-induced polydipsia in rats: Role of NMDA, sigma-1, and 5-HT receptors.
Madeline T Van Fossen, Alexia G Dalton, Adam J Prus
Pharmacology, Biochemistry, and Behavior May 29, 2026 DOI: 10.1016/j.pbb.2026.174218 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Food-restricted rats |
| Interventions | Dextromethorphan DOI SA4503 racemic ketamine M100907 NMDA BD1047 |
| Topics | Serotonin |
| Keywords | Dextromethorphan Nmda receptors Obsessive-compulsive disorder Rats Schedule-induced polydipsia Sigma-1 receptors |
| Key findings | Dextromethorphan dose-dependently reduced compulsive-like water consumption in both low and high drinker rats in a schedule-induced polydipsia paradigm. |
Abstract
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.
Comparable studies
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| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cites 4
- Dextromethorphan-Bupropion for the Treatment of Depression: A Systematic Review of Efficacy and Safety in Clinical Trials. CNS Drugs October 1, 2023
- Dextromethorphan-bupropion (Auvelity) for the Treatment of Major Depressive Disorder Clinical Psychopharmacology and Neuroscience July 17, 2023
- Do psychoactive drugs have a therapeutic role in compulsivity? Studies on schedule-induced polydipsia. Psychopharmacology February 2018
- 5-HT_2A and 5-HT_2C Receptors Exert Opposing Effects on Locomotor Activity in Mice Neuropsychopharmacology July 1, 2009