[The threshold lowering effects of chronic treatment with haloperidol on beta-carboline derivative-induced tonic...

To clarify a relationship between dopamine neuron and purine, GABA or benzodiazepine system, we have studied the changes in the threshold of tonic convulsion induced by each antagonist after chronic treatment with haloperidol in mice. Mice were given haloperidol (1 mg/kg, sc) once a day for 19 d and challenged with caffeine (an adenosine receptor antagonist), beta-DMCM (beta-carboline derivative: as a benzodiazepine receptor antagonist), picrotoxin (a Cl- channel blocker) or bicuculline (a GABAa receptor antagonist) 30 min, 24 h and 48 h after the last injection of haloperidol. Only the threshold of beta-DMCM-induced tonic convulsion was lowered and it was reversed 7 d after the last injection. The beta-DMCM-induced convulsions on 2 d withdrawal were reversed by diazepam (2.5 mg/kg, ip; a benzodiazepine receptor agonist), Ro15-1788 (5.0 mg/kg, ip; as like a benzodiazepine receptor partial agonist), muscimol (2.0 mg/kg, ip; a GABAa receptor agonist) or apomorphine (0.25 and 2.0 mg/kg, ip; a dopamine receptor agonist). These results suggest that the lowering effect of chronic haloperidol on seizure threshold may be involved in the development of tolerance to haloperidol. It may implicate in direct interactions between benzodiazepine and dopamine or GABA systems but may not between dopamine and GABA neurons in development of lowering seizure threshold following chronic haloperidol treatment.