The role of glutamate receptors in antipsychotic drug action

It has recently been postulated that disturbances in glutamatergic neurotra nsmission may contribute to the pathophysiology of schizophrenia. Therefore the aim of the present study was to evaluate the role of glutamate NMDA an d group II metabotropic receptors in the antipsychotic drug action. To this aim the influence of some well-known neuroleptics on cortical NMDA recepto rs was examined. Furthermore, their behavioral effects were compared with t hose of the novel agonist of group II glutamate metabotropic receptors, LY 354740, in some animal models of schizophrenic deficits. We found that long -term administration of the typical neuroleptic haloperidol and the atypica l one clozapine increased the number of NMDA receptors labelled with [H-3]C GP 39653 in different cortical areas. Long-, but not short-term, treatment with haloperidol and raclopride diminished the deficit of prepulse inhibiti on produced by phencyclidine, which is a model of sensorimotor gating defic it in schizophrenia. In contrast, neither short- nor long-term treatment wi th clozapine influenced the phencyclidine effect in that model. Acute treat ment with LY 354740 reversed neither (1) the deficit of prepulse inhibition produced by phencyclidine or apomorphine, nor (2) the impairment in a dela yed alternation task induced by MK-801, which is commonly used to model the frontal lobe deficits associated with schizophrenia. The present study sug gests that an increase in the density of cortical NMDA receptors may be imp ortant to a longterm neuroleptic therapy. Conversely, the results do not su pport the role of group II metabotropic glutamate receptors in the antipsyc hotic drug action.