COCAINE - EVIDENCE FOR NMDA-MEDIATED, BETA-CARBOLINE-MEDIATED AND DOPAMINERGIC-MEDIATED SEIZURES IN MICE

The present study was undertaken to examine the role of the benzodiaze pine/GABA and N-methyl-D-aspartate (NMDA) systems in the convulsive ef fect of cocaine in mice. When cocaine (3.5 mg/ml) solution was infused into the tail vein at a rate of 0.3 ml/min, mice showed clonic and to nic convulsions. These seizures were not affected by low doses of bicu culline or picrotoxin, a GABA(A) receptor antagonist and a Cl ion chan nel blocker, respectively. Aminooxyacetic acid (AOAA), a GABA deaminas e inhibitor, and phenobarbital, a Cl ion channel activator, and baclof en, a GABA(B) receptor agonist, also had no effect on these convulsion s. Benzodiazepine inverse agonist beta-DMCM, at a dose which by itself had no convulsive effect lowered the convulsive threshold of cocaine. This lowered convulsive threshold was reversed by flumazenil, a benzo diazepine inverse antagonist, and diazepam, a benzodiazepine full agon ist, which by themselves did not inhibit cocaine seizure. It is Likely that cocaine seizure involves a benzodiazepine( beta-carboline) recog nition site other than the benzodiazepine/GABA(A) receptor-Cl ionophor e complex system. CPP and MK-801, competitive and noncompetitive NMDA receptor antagonists, respectively, inhibited cocaine seizures. The in hibitory effects of CPP on cocaine convulsion were reversed by a low d ose of NMDA, which by itself did not induce seizure. A dopamine D-1 re ceptor agonist SKF38393 enhanced both clonic and tonic convulsions, wh ile a dopamine D-2 receptor agonist bromocriptine inhibited these conv ulsions. These stimulatory and inhibitory effects were reversed by the D-1 and D-2 receptor antagonists, SCH23390 and haloperidol, respectiv ely. These results suggest that the cocaine-induced convulsion may inv olve an activation of the NMDA-Ca ionophore complex system, which is m ediated by the dopaminergic system, and a beta-carboline recognition s ite other than the benzodiazepine/GABA(A) receptor-Cl ionophore comple x system. (C) 1998 Elsevier Science B.V. All rights reserved.