Modulators of N-methyl-D-aspartate protect against diazepam- or phenobarbital-resistant cocaine convulsions.
The anticonvulsants diazepam (1-10 mg/kg) and phenobarbital (30-100 mg/kg) protected against lethality without altering clonic convulsions induced by 75 mg/kg cocaine (CD100) in male Swiss Webster mice. In contrast, the non-competitive N-methyl-D-aspartate (NMDA) antagonists, MK-801 (dizocilpine) and phencyclidine, produced dose-dependent protection against cocaine convulsions. The competitive NMDA antagonists, CPP and NPC 12626, were also anti-convulsant, without producing the behavioral disturbances associated with non-competitive antagonists. Diazepam and phenobarbital protected against convulsions induced by 60 mg/kg cocaine (90% convulsions alone). Compounds that act at the strychnine-insensitive glycine receptor of the NMDA receptor complex, ACPC and 7-chlorokynurinic acid, also protected against convulsions induced by 60 mg/kg cocaine. In contrast, the non-opioid antitussive anticonvulsants (dextromethorphan, caramiphen, and carbetapentane) were not active against either dose of cocaine. The efficacy of compounds as antagonists of the convulsant effects of cocaine and NMDA appear related. These results suggest a potential role for the NMDA receptor complex in the convulsant actions of cocaine and new molecular targets for drug discovery in treating cocaine toxicity.
Witkin
J M
JM
Drug Development Group, Psychobiology Laboratory, NIDA Addiction Research Center, Baltimore, MD 21224.
Tortella
F C
FC
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants; D003042:Cocaine / Q000633:toxicity*; D003975:Diazepam / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D008297:Male; D051379:Mice; D010622:Phencyclidine / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology*; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D013997:Time Factors
D000596:Amino Acids; D000927:Anticonvulsants; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; C060212:NPC 12626; D016291:Dizocilpine Maleate; D003042:Cocaine; D010622:Phencyclidine; D003975:Diazepam; D010634:Phenobarbital