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 neurotransmitter for NMDA receptors, pharmacological interventions to lower glutamatergic activity through non-NMDA ionotropic receptor-mediated mechanisms were 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-4-proprionic acid (AMPA)/kainate receptor antagonists 1,2,3,4-tetrahydro-6-nitro-2, 3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX; 10-80 mg/kg, i.p.) or 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2, 3-benzodiazepine hydrochloride (GYKI 52466; 10-20 mg/kg, i.p.) failed to significantly attenuate cocaine-induced convulsions or lethality. Although ineffective when administered alone, NBQX enhanced the protective effects of 5-nitro-6,7-dichloro-1, 4-dihydro-2,3-quinoxalinedione (ACEA-1021), an 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 the convulsive effects of cocaine. The data suggest that AMPA/kainate receptors indirectly influence the pathophysiological changes that occur after a cocaine overdose through modulation of NMDA receptors.
Pouw
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University of Oklahoma Health Sciences Center, College of Pharmacy, Department of Pharmacology and Toxicology, P.O. Box 26901, Oklahoma City, OK 73190, USA.
Nour
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Matsumoto
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D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use; D001569:Benzodiazepines; D003042:Cocaine; D004359:Drug Therapy, Combination; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D011810:Quinoxalines / Q000627:therapeutic use; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*
D014151:Anti-Anxiety Agents; D001569:Benzodiazepines; D003042:Cocaine; D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; C061950:GYKI 52466; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C092062:licostinel