Influence of long-lasting administration of neuroleptics on cortical NMDA receptors and phencyclidine-induced deficit in the sensorimotor gating in rats.

The aim of this study was to examine the role of cortical NMDA receptors in the antipsychotic action of neuroleptics. Haloperidol (1 mg/kg/day) and clozapine (30 mg/kg/day) were administered to rats in drinking water. Autoradiographic and saturation binding analyses showed that a 3-month treatment with both haloperidol and clozapine increased the density of NMDA receptors labelled with [3H]CGP 39653 (a competitive antagonist) in the parietal and insular cortices. Haloperidol additionally increased the binding of that ligand in the frontal cortex. None of those neuroleptics influenced the binding of [3H]MK-801, an uncompetitive antagonist of NMDA receptors, in the frontal, parietal or insular cortices. A 6-week and a 3-month treatment with haloperidol antagonized the deficit of prepulse inhibition induced by phencyclidine (5 mg/kg s.c.). In contrast, short-term (4-day) administration of that neuroleptic was ineffective. The present study suggests that the increased density of cortical NMDA receptors, induced by long-term neuroleptic administration, may overcome the deficit of sensorimotor gating induced by phencyclidine. However, contribution of such an effect to the antipsychotic activity needs to be established.