Novel NMDA/glycine site antagonists attenuate cocaine-induced behavioral toxicity.
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.
Matsumoto
R R
RR
Department of Pharmacology and Toxicology, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City 73190, USA.
Brackett
R L
RL
Kanthasamy
A G
AG
D000818:Animals; D003042:Cocaine / Q000633:toxicity*; D019970:Cocaine-Related Disorders / Q000150:complications / Q000517:prevention & control*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011810:Quinoxalines / Q000494:pharmacology*; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000209:etiology / Q000517:prevention & control
C093392:ACEA 1328; D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; C092062:licostinel; D003042:Cocaine