Differential effects of chronic haloperidol and clozapine administration on glutamatergic transmission in the fronto-parietal cortex in rats: microdialysis and electrophysiological studies

Glutamatergic neurotransmission has been suggested to be involved in the pathogenesis of schizophrenia. Hence the aim of the present study was to examine the influence of haloperidol, a typical neuroleptic, and clozapine, an atypical one, on glutamatergic transmission in the fronto-parietal cortex. Haloperidol (1 mg/kg per day), or clozapine (30 mg/kg per day), was administered in drinking water for 6 weeks and was afterwards withdrawn for 4 days. The basal and the veratridine (100 muM)-induced extracellular glutamate and aspartate levels were measured by a microdialysis in vivo; neuronal discharges which developed in a Mg2+-free medium were recorded extracellularly in cortical slices ex vivo. Haloperidol elevated the basal, but not the veratridine-stimulated, extracellular levels of glutamate and aspartate. Haloperidol enhanced the activity of cortical neurons, which resulted in a decrease in the inhibitory influence of CGP 37849 on their frequency. The increased frequency of discharges induced by NMDA was not affected by haloperidol. In contrast, clozapine lowered both the basal and the stimulated levels of glutamate and aspartate, but had no effect on the activity of cortical neurons. The present study suggests that the two representatives of typical and atypical neuroleptics affect differently glutamatergic neurotransmission in the fronto-parietal cortex, which may reflect their diverse efficacy as antipsychotic agents.