PALLIDAL GABA AND ATYPICALITY OF ANTIPSYCHOTIC DRUGS

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Atypical anti-psychotic drugs (APDs) are primarily differentiated from typical APDs in that they possess a lower motor side effects profile. Experimental approaches to study "atypicality" have generally focused on cortical, striatal, and limbic dopamine terminal regions of the brain. However,, research findings on motor syndromes and psychosis also support the critical role of striatopallidal gamma-aminobutyric acid (GABA) pathways. Our specific global hypothesis is that decreases in pallidal GABA function mediate the atypical profile of certain APDs and may be a critical mechanism for the low incidence of motor side effects. Recent data from our laboratory has shown that typical APDs (e.g. haloperidol) produce motor side effects and increase GABA release in the globus pallidus, while atypical APDs (e.g. clozapine) produce minimal motor side effects and decrease GABA release in the globus pallidus. Furthermore, only clozapine has an effect on decreasing GABA in the ventral pallidum, a pallidal subregion believed to preferentially mediate "limbic" striatal output. The effect of atypical APDs may result form an inhibition of presynaptic release of GABA, since the density of nerve terminal GABA immunolabeling is increased after clozapine injection. This paradigm of altered GABA release in pallidal pathways could provide clues regarding the low incidence of motor side effects with atypical APDs and further our understanding of pallidal GABA in mediating atypical APD action. The series of studies proposed here will utilize a rodent model of acute and chronic APD administration to answer several questions. The first set of experiments will examine changes in extracellular and presynaptic pallidal GABA after systematic and site- specific administration of drugs with a high or low motor side effect profile. In order to test the possibility that 5-HT2 receptor subtypes play a role in mediating pallidal GABA function, a second series of experiments will assess 5-HT2A and 5-HT2C receptor agonism and antagonism on pallidal GABA function. In a final set of studies, pallidal GABA function and motor activity will be studied after prolonged periods of APD administration which are similar to the treatment durations utilized in psychotic patients. These studies will provide new insights on the mechanisms of action of APDs and provide a novel means of identifying putative atypical APDs. The information obtained will facilitate the development of optimal pharmacotherapy for mental disorders, particularly schizophrenia.