Subchronic treatment with either clozapine, olanzapine or haloperidol produces a hyposensitive response of the rat cortical cells to N-methyl-D-aspartate

Using the technique of intracellular recording in in vitro brain slice prep arations, we examined the effects produced by repeated administration of th e antipsychotic drugs clozapine, olanzapine and haloperidol, on N-methyl-D- aspartic acid-induced responses in pyramidal cells of the rat medial prefro ntal cortex. Rats were anesthetized and decapitated 24 h after the conclusi on of daily intraperitoneal injection with either clozapine (25 mg/kg), ola nzapine (1, 5 or 10 mg/kg) or haloperidol (0.5 mg/kg) for 21 days, and the slices from medial prefrontal cortex were used for electrophysiological rec ordings. The concentration-response curves for N-methyl-D-aspartic acid to activate cortical cells shifted markedly to the right in rats which receive d the subchronic antipsychotic drug treatment, compared with those obtained from rats which received repeated injections of vehicle (1 ml/kg/day, i.p. for 21 days). In addition, repeated exposure to antipsychotic drugs caused a significant reduction in the ability of these antipsychotic drugs to aug ment the N-methyl-D-aspartic acid-induced inward current in pyramidal cells of the rat medial prefrontal cortex. Repeated administration of haloperido l, but nor clozapine or olanzapine, significantly hyperpolarized the restin g membrane potential and increased membrane resistance in pyramidal cells o f the medial prefrontal cortex. Moreover, subchronic treatment with haloper idol, but not clozapine or olanzapine, depressed (+/-)-alpha-amino-3-hydrox y-5-methylisoxazole-4-propionic acid-induced responses. The desensitized re sponse of medial prefrontal cortex cells to N-methyl-D-aspartic acid could be the result of a compensatory response to the facilitating action of anti psychotic drugs on N-methyl-D-aspartic acid receptor-mediated transmission. The inhibitory action of haloperidol on (+/-)-alpha-amino-3-hydroxy-5-meth ylisoxazole-4-propionic acid responses map also contribute to the rightward shift of the N-methyl-D-aspartic acid concentration-response curve. Thus, the present study suggests that the atypical antipsychotic drugs, clo zapine and olanzapine, as well as the typical antipsychotic drug haloperido l strongly modulate glutamatergic transmission after prolonged treatment. T his might be an important factor in the mechanisms by which these drugs all eviate symptoms in schizophrenic patients. (C) 2000 IBRO. Published by Else vier Science Ltd. All rights reserved.