Anticonvulsant efficacy of N-methyl-D-aspartate antagonists against convulsions induced by cocaine

Convulsions associated with cocaine abuse can be life threatening and resis tant to standard emergency treatment. Cocaine (75 mg/kg, i.p.) produced clo nic convulsions in similar to 90% of male, Swiss-Webster mice. A variety of clinically used antiepileptic agents did not significantly protect against cocaine convulsions (e.g., diazepam and phenobarbital). Anticonvulsants in clinical practice that did significantly protect against convulsion did so only at doses with significant sedative/ataxic effects (e.g., clonazepam a nd valproic acid). In contrast, functional N-methyl-D-aspartate (NMDA) anta gonists all produced dose-dependent and significant protection against the convulsant effects of cocaine. Anticonvulsant efficacy was achieved by bloc kade of both competitive and noncompetitive modulatory sites on the NMDA re ceptor complex. Thus, competitive antagonists, ion-channel blockers, polyam ine antagonists, and functional blockers of the strychnine-insensitive glyc ine modulatory site all prevented cocaine seizures. The role of NMDA recept ors in the control of cocaine-induced convulsions was further strengthened by the positive correlation between the potencies of noncompetitive antagon ists or competitive antagonists to block convulsions and their respective a ffinities for their specific binding sites on the NMDA receptor complex. Al though some NMDA blockers produced profound behavioral side effects at effi cacious doses (e.g., noncompetitive antagonists), others (e.g., some low-af finity channel blockers, some competitive antagonists, and glycine antagoni sts) demonstrated significant and favorable separation between their antico nvulsant and side effect profiles. The present results provide the most ext ensive evidence to date identifying NMDA receptor blockade as a potential s trategy for the discovery of agents for clinical use in averting toxic sequ elae from cocaine overdose. Given the literature suggesting a role for thes e drugs in other areas of drug abuse treatments, NMDA receptor antagonists sit in a unique position as potential therapeutic candidates.