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

Abstract

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.

• Authors: B Pouw, M Nour, R R Matsumoto
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 386 Issue 2-3 Pg. 181-6 (Dec 15 1999) ISSN: 0014-2999 [Print] Netherlands
• PMID: 10618468 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Anxiety Agents
• Excitatory Amino Acid Antagonists
• Quinoxalines
• Receptors, AMPA
• Receptors, Kainic Acid
• GYKI 52466
• 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
• Benzodiazepines
• licostinel
• Cocaine

Topics

• Animals
• Anti-Anxiety Agents (therapeutic use)
• Benzodiazepines
• Cocaine
• Drug Therapy, Combination
• Excitatory Amino Acid Antagonists (therapeutic use)
• Male
• Mice
• Quinoxalines (therapeutic use)
• Receptors, AMPA (antagonists & inhibitors)
• Receptors, Kainic Acid (antagonists & inhibitors)
• Seizures (chemically induced, drug therapy)