Glutamate receptor antagonists block cocaine-induced convulsions and death.
The involvement of excitatory amino acid (EAA) receptors in mediation of the toxic effects of cocaine was studied in male ICR mice. Cocaine HCl (90 mg/kg, IP) induced seizures in 95% and death within 24 h in 68% (n = 135) of the animals. There was a significant correlation (r = .54) between the time to onset of convulsions and the time to death in mice which died within 30 min of injection (n = 84). Pretreatment with selected EAA receptor antagonists 15 min prior to cocaine differentially blocked cocaine toxicity. Selective N-methyl-D-aspartic acid (NMDA) receptor antagonists (MK-801, dextrorphan, CPP) decreased both the incidence of seizures and mortality. A nonselective EAA antagonist, kynurenic acid, decreased lethality in doses which did not reduce convulsions. A similar action was observed following pretreatment with the selective kainic acid/AMPA receptor antagonist, GDEE. Antagonists at EAA receptors can provide significant protection against cocaine-induced toxicity. Moreover, the data provide evidence for the involvement of both NMDA and non-NMDA receptor subtypes in aspects of cocaine toxicity.
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216-4505.
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D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D003042:Cocaine / Q000633:toxicity*; D003643:Death; D003917:Dextrorphan / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005971:Glutamates / Q000378:metabolism / Q000494:pharmacology*; D007736:Kynurenic Acid / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010879:Piperazines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors* / Q000502:physiology; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*; D013997:Time Factors
D000927:Anticonvulsants; D005971:Glutamates; D010879:Piperazines; D011810:Quinoxalines; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D003917:Dextrorphan; C011829:glutamic acid diethyl ester; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D007736:Kynurenic Acid; D003042:Cocaine