NOVEL NMDA GLYCINE SITE ANTAGONISTS ATTENUATE COCAINE-INDUCED BEHAVIORAL TOXICITY/

N-Methyl-D-aspartate (NMDA)/glycine site antagonists were tested for t heir ability to prevent cocaine-induced convulsions and lethality in S wiss Webster mice. Pre-treatment of mice with the novel NMDA/glycine s ite antagonists ACEA-1021 tro-6,7-dichloro-1,4-dihydro-2,3-quinoxaline dione) or ACEA-1328 tro-6,7-dimethyl-1,4-dihydro-2,3-quinoxalinedione) attenuated cocaine-induced convulsions; these effects were pharmacolo gically antagonized with D-cycloserine. The structurally-related NMDA/ glycine site antagonist DCQX (6,7-dichloroquinoxaline-2,3-dione) and t he structurally-unrelated NMDA/glycine site partial agonist HA-966 (3- amino-1-hydroxy-2-pyrrolidinone) also attenuated cocaine-induced convu lsions, with the R(+)-isomer of HA-966 being more effective than the S (-)-isomer. In contrast, the selective pha-amino-3-hydroxy-5-methyliso xazole-4-proprionic acid (AMPA) receptor antagonist, NBQX itro-2,3-dio xo-benzo[f]quinoxaline-7-sulfonamide), failed to provide statistically significant protection although it shares the 2,3-quinoxalinedione st ructure of DCQX and the ACEA compounds. Pre-treatment with ACEA-1021, ACEA-1328, DCQX, or R(+)-HA-966 also attenuated cocaine-induced lethal ity 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 vehic le resulted in death of all mice, The results suggest the utility of t argeting excitatory mechanisms for the treatment of cocaine overdose a nd offer a novel base structure from which effective pharmacotherapies can be developed. (C) 1997 Elsevier Science B.V.