Neurochemical Adaptation to Chronic Antipsychotics

Gale, Karen

Abstract

The influence of dopaminergic (DA) transmission on the function of output pathways from the basal ganglia will be studied using neurochemical techniques. In particular, we will characterize DA-related changes in the utilization of GABA in the target areas (tegmentum and tectum) of nigral descending projections. The role of synaptic transmission in substantia nigra (with emphasis on GABA and substance P) for mediating the influence of antipsychotic drugs on the descending nigral GABA projections will be evaluated. In addition, we will examine the relative influence of substance P for regulating DA synthesis and metabolism in efferents from SN to striatum in rats treated acutely or chronically with antipsychotic drugs. We have previously demonstrated that striatonigral GABA projections are under the influence of DA neurons and that neurochemical indices of pre- and post-synaptic GABA activity in substantia nigra are altered by chronic interference with striatal DA transmission. These studies will now be extended to evaluate pre- and post-synaptic indices of GABA utilization in the nigrotegmental and nigrotectal projections of rats treated chronically with classical and atypical antipsychotic drugs. These descending nigral efferents will also be evaluated for their role in mediating DA-evoked behavioral responses; we will attempt to relate these behaviors to the neurochemical changes obtained. Our results will help delineate selected circuits and pathways which may alter their function in response to long-term exposure to antipsychotic drugs. Chronic changes in these pathways may be responsible for some of the long-term therapeutic and/or adverse effects of antipsychotic drug treatment.