Prevention of cocaine-induced convulsions and lethality in mice: effectiveness of targeting different sites on the NMDA receptor complex

N-methyl-D-aspartate (NMDA) receptors appear to be involved in the behavior al toxic effects of cocaine. Therefore, different classes of NMDA receptor antagonists were compared for their ability to attenuate cocaine-induced co nvulsions and lethality in male, Swiss Webster mice. The mice were pre-trea ted (i.p.) with vehicle or an antagonist from one of the following classes: NMDA/glycine site antagonist (7-chlorokynurenic acid, ACEA-1021, ACEA-1031 , ACEA-1328, DCQX, R(+)-HA-966), competitive antagonist (CPP, D-AP7), chann el blocker (MK-801, memantine), or allosteric modulator (ifenprodil, CP-101 ,606, Co 101022, haloperidol). After a 15 min pre-treatment period, the mic e were administered a convulsive (60 mg/kg, i.p.) or lethal (125 mg/kg, i.p .) dose of cocaine, equivalent to the calculated ED/LD97 values. Pre-treatm ent with competitive or NMDA/glycine site antagonists dose-dependently atte nuated cocaine-induced convulsions and lethality (P < 0.05). Pre-treatment with channel blockers or allosteric modulators of the NMDA receptor protect ed against cocaine-induced convulsions (P < 0.05), but were ineffective or less effective than the competitive and glycine site antagonists in prevent ing death. The glutamate release inhibitor riluzole failed to prevent both the convulsions and lethality induced by cocaine. Significantly, post-treat ment with NMDA/glycine site antagonists (ACEA-1021, ACEA-1031, ACEA-1328) a fter a cocaine overdose prevented death in a significant number of animals. The data suggest that NMDA receptors are involved in the pathophysiology o f a cocaine overdose. (C) 2000 Elsevier Science Ltd. All rights reserved.