RELATIONSHIP OF EXTRACELLULAR DOPAC TO DOPAMINE RELEASE

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In order to understand the relationship of dopamine (DA) release to behavior, studies in which DA release, or an index of DA release, is monitored in intact animals are needed to complement studies using lesions of dopaminergic systems to produce behavioral deficits. One approach to the problem of monitoring DA release has been to use metabolite levels as indices of DA release. In order to use metabolite information effectively, the relationship of the extracellular levels of the metabolite to neurotransmitter release must be known. In the present proposal a model of the relationship of extracellular dihydroxyphenylacetic acid (DOPAC) to dopamine release is described and several experiments to test the model are proposed. In particular, in vivo voltammetry will be used to determine the kinetics of dopamine metabolism to extracellular DOPAC. This approach represents a new, nonpharmacological method for studying the regulation of neurotransmitter release. Rate constants for formation of DOPAC and its clearance from the extracellular space will be determined. This will be done by nonlinear regression on voltammetric data representing the increase in extracellular DOPAC following very brief electrical stimulation of the nigrostriatal dopaminergic pathway. The voltammetric data will be validated by high performance liquid chromatography of the extracellular fluid. The relative time course of dopamine release and change in extracellular DOPAC will be examined with regard to the use and limitations of using metabolite information as a temporal index of neurotransmitter release. Additionally, fundamental information on the dynamics of the intact nigrostriatal dopaminergic system will be obtained that is not possible to acquire by any other method.