Effects of AMPA/kainate glutamate receptor antagonists on cocaine-induced convulsions and lethality in mice

Prior studies demonstrate that NMDA receptor antagonists attenuate cocaine- induced convulsions and lethality. Since glutamate is the primary neurotran smitter for NMDA receptors, pharmacological interventions to lower glutamat ergic activity through non-NMDA ionotropic receptor-mediated mechanisms wer e evaluated for their ability to prevent the convulsive and lethal effects of cocaine. Pre-treatment of male, Swiss Webster mice with the alpha-amino- 3-hydroxy-5-methylisoxazole-3-proprionic acid (AMPA)/kainate receptor antag onists 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7sulfonamid e (NBQX; 10-80 mg/kg, i.p.) or 1-(4-aminophenyl)-4-methyl-7,8-methylenediox y-5H-2,3-benzodiazepine hydrochloride (GYKI 52466; 10-20 mg/kg, i.p.) faile d to significantly attenuate cocaine-induced convulsions or lethality. Alth ough ineffective when administered alone, NBQX enhanced the protective effe cts of 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (ACEA-1021), a n NMDA/glycine site antagonist, when administered in combination. The mixed NMDA/non-NMDA receptor competitive antagonist 5-chloro-7-trifluoromethyl-1 ,2,3,4-tetrahydroquinoxaline-2,3-dione (ACEA-1011) also protected against t he convulsive effects of cocaine. The data suggest that AMPA/kainate recept ors indirectly influence the pathophysiological changes that occur after a cocaine overdose through modulation of NMDA receptors. (C) 1999 Elsevier Sc ience B.V. All rights reserved.