Potentiation of DOM-induced stimulus control by non-competitive NMDA antagonists: a link between the glutamatergic and serotonergic hypotheses of schizophrenia.

In rats trained to recognize the drug DOM (a hallucinogen), giving them NMDA receptor antagonists (PCP, dizocilpine, or ketamine) before DOM made DOM's effects stronger. DOM alone at a low dose produced 32% of responses indicating drug recognition, but when combined with the NMDA antagonists, responses rose to 73-84%. The NMDA antagonists alone produced only 13-36% drug-like responses. The findings suggest that blocking NMDA glutamate receptors enhances DOM's effects, and the authors propose that drug discrimination techniques could help integrate theories about the causes of psychotic disorders.

Study at a glance

Abstract

The present investigation examined the interaction between 2,5-dimethoxy-4-methylamphetamine [DOM] and non-competitive NMDA antagonists in rats trained with DOM [0.6 mg/kg; 75 min pretreatment time] as a discriminative stimulus. Pretreatment with phencyclidine [PCP] at a dose of 3 mg/kg shifted the DOM dose-response relationship to the left. When a fixed dose of DOM [0.1 mg/kg] which by itself yielded 32% DOM-appropriate responding was combined with a range of doses of PCP, dizocilpine, and ketamine, DOM-appropriate percentages increased to maxima of 73%, 84%, and 79%, respectively. When given alone, PCP, dizocilpine, and ketamine were followed by maxima of 36%, 15%, and 13%, respectively. It is concluded that the effects of DOM as a discriminative stimulus are potentiated by pretreatment with non-competitive antagonists of glutamate receptors of the NMDA subtype. These data suggest that the application of the technique of drug-induced stimulus control may prove useful in the reconciliation and integration of current hypotheses as to the etiology of psychotic disorders.