Dopamine (DA) receptor systems are related to the mechanism of action of antipsychotic drugs, and to their sometimes serious neurological side effects, such as tardive dyskinesia. The proposal continues our long-term objectives of elucidating the basic molecular and neuropharmacological properties of forebrain DA systems, and discovering relationships between these properties and the psychopharmacological effects of drugs used to treat the most severely ill psychiatric patients.
The specific aims of this project focus on elaborating and clarifying subtle but extremely important differences that have been discovered in various DA systems in mammalian brain. Specifically, we propose to elucidate the neuropharmacological differences between DA systems located in the nigrostriatal, mesolimbic, and mesocortical regions. We will also continue to explore genetic differences in DA systems in mouse strains, and undertake an in depth investigation of changes that occur in regional DA systems during development. These studies are important in advancing our understanding of the etiology and treatment of psychotic disorders such as schizophrenia, and neuropsychiatric disorders such as Parkinson's and Huntington's diseases and Tourette's syndrome, as well as the spontaneous and drug-induced dyskinesias. These studies will exploit several new techniques and discoveries. Of particular importance has been the design and synthesis of a novel class of chemical agents, the optical S(+)-isomers of apomorphine, that appear to interact selectively with limbic DA systems, and promise to provide a potential breakthrough in the development of safer antipsychotic agents. Newer related agents, including radioactive tracers, will be synthesized as chemical probes to determine the basis for this selectivity, and to further characterize DA receptors. They will be studied for effects on regional dopamine binding and metabolism, as well as actions on regional energy utilization using chromatographic and autoradiographic techniques with brain homogenates and slices. Developmental studies will concentrate on the marked changes in DA metabolism, turnover, and autoreceptor function that occur with maturation and aging, and will provide important information on the long-term effects of these agents on neural systems.
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