The effect of chronic treatment with antipsychotic drugs will be examined in rats with respect to alterations in neurochemical parameters in selected brain regions. An attempt will be made to discriminate changes which are related to behavioral alterations induced by the drugs. In particular, dopamine-containing, GABA-containing and Substance-P-containing pathways within the basal ganglia and GABA-containing outputs from the basal ganglia will be manipulated pharmacologically and the resulting neurochemical and behavioral effects will be compared. Neurochemical parameters to be examined include GABA receptor binding, GABA turnover, and enzymes associated with GABA synthesis and degradation. Behavioral parameters under study include stereotyped hyperactivity induced by dopamine stimulants or intranigral application of GABA agonists, and catalepsy induced by antipsychotic drugs. Both acute and chronic drug treatments will be compared in order to distinguish between short-term and long-term influences of the drugs on the neural circuits of interest. In certain cases, a neural pathway and its target region will be characterized neurochemically and anatomically before examining the influence of antipsychotic drug treatment on the pathway. Emphasis will be placed on research, on expanding the existing methodological and technical capabilities of the laboratory, and on developing additional techniques applicable to the proposed area of investigation. Skills to be expanded and developed include quantitative histochemical procedures for neurotransmitter-associated enzymes, neuroanatomical tracing techniques, high pressure liquid chromatography, procedures for monitoring neurotransmitter synthesis and release in brain slices, methods for transplantation of fetal rat brain nuclei or adrenal chromaffin cells into adult rat brain, radiolabelling of GABA-transaminase for purposes of examining its activity and transport in vivo, and radioimmunoassay procedures for analysis of pepetides.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Scientist Development Award - Research (K02)
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Research Scientist Development Review Committee (MHK)
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Georgetown University
School of Medicine & Dentistry
United States
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Segovia, J; Tillakaratne, N J; Whelan, K et al. (1990) Parallel increases in striatal glutamic acid decarboxylase activity and mRNA levels in rats with lesions of the nigrostriatal pathway. Brain Res 529:345-8
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