Novel NMDA/glycine site antagonists attenuate cocaine-induced behavioral toxicity.

Abstract

N-Methyl-D-aspartate (NMDA)/glycine site antagonists were tested for their ability to prevent cocaine-induced convulsions and lethality in Swiss Webster mice. Pre-treatment of mice with the novel NMDA/glycine site antagonists ACEA-1021 (5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione) or ACEA-1328 (5-nitro-6,7-dimethyl-1,4-dihydro-2,3-quinoxalinedione) attenuated cocaine-induced convulsions; these effects were pharmacologically antagonized with D-cycloserine. The structurally-related NMDA/glycine site antagonist DCQX (6,7-dichloroquinoxaline-2,3-dione) and the structurally-unrelated NMDA/glycine site partial agonist HA-966 (3-amino-1-hydroxy-2-pyrrolidinone) also attenuated cocaine-induced convulsions, with the R(+)-isomer of HA-966 being more effective than the S(-)-isomer. In contrast, the selective alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) receptor antagonist, NBQX (1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide) , failed to provide statistically significant protection although it shares the 2,3-quinoxalinedione structure of DCQX and the ACEA compounds. Pre-treatment with ACEA-1021, ACEA-1328, DCQX, or R(+)-HA-966 also attenuated cocaine-induced lethality in mice. Significantly, post-treatment with ACEA-1021, immediately prior to or after the onset of seizures, prevented death in up to 86% of mice receiving a lethal dose of cocaine; post-treatment with vehicle resulted in death of all mice. The results suggest the utility of targeting excitatory mechanisms for the treatment of cocaine overdose and offer a novel base structure from which effective pharmacotherapies can be developed.

• Authors: R R Matsumoto, R L Brackett, A G Kanthasamy
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 338 Issue 3 Pg. 233-42 (Nov 12 1997) ISSN: 0014-2999 [Print] Netherlands
• PMID: 9424017 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ACEA 1328
• Excitatory Amino Acid Antagonists
• Quinoxalines
• Receptors, Glycine
• Receptors, N-Methyl-D-Aspartate
• licostinel
• Cocaine

Topics

• Animals
• Cocaine (toxicity)
• Cocaine-Related Disorders (complications, prevention & control)
• Excitatory Amino Acid Antagonists (pharmacology)
• Male
• Mice
• Quinoxalines (pharmacology)
• Receptors, Glycine (antagonists & inhibitors)
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors)
• Seizures (etiology, prevention & control)