The present study was undertaken to examine the role of the benzodiazepine/GABA and N-methyl-d-aspartate (NMDA) systems in the convulsive effect 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 tonic convulsions. These seizures were not affected by low doses of bicuculline or picrotoxin, a GABAA receptor antagonist and a Cl ion channel blocker, respectively. Aminooxyacetic acid (AOAA), a GABA deaminase inhibitor, and phenobarbital, a Cl ion channel activator, and baclofen, a GABAB receptor agonist, also had no effect on these convulsions. 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 benzodiazepine inverse antagonist, and diazepam, a benzodiazepine full agonist, which by themselves did not inhibit cocaine seizure. It is likely that cocaine seizure involves a benzodiazepine (beta-carboline) recognition site other than the benzodiazepine/GABAA receptor-Cl ionophore complex system. CPP and MK-801, competitive and noncompetitive NMDA receptor antagonists, respectively, inhibited cocaine seizures. The inhibitory effects of CPP on cocaine convulsion were reversed by a low dose of NMDA, which by itself did not induce seizure. A dopamine D1 receptor agonist SKF38393 enhanced both clonic and tonic convulsions, while a dopamine D2 receptor agonist bromocriptine inhibited these convulsions. These stimulatory and inhibitory effects were reversed by the D1 and D2 receptor antagonists, SCH23390 and haloperidol, respectively. These results suggest that the cocaine-induced convulsion may involve an activation of the NMDA-Ca ionophore complex system, which is mediated by the dopaminergic system, and a beta-carboline recognition site other than the benzodiazepine/GABAA receptor-Cl ionophore complex system.
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