Research is proposed which will further investigate the basis for behavioral/motor recovery following striatal dopamine (DA) depletion in cats administered the toxin MPTP. Previous work showed that motor recovery occurs in previously parkinsonian cats despite no significant recovery of tissue levels of DA in the dorsal striatum. Pilot studies using microdialysis though have shown that recovered cats have significantly recovered dorsal striatal extracellular fluid (ECF) DA levels which is not reflected in the tissue neurochemistry. Since post mortem neurochemistry does not seem to reflect the functional integrity of the striatum in recovered cats, in vivo microdialysis experiments are proposed to study whether there is a causal relationship between ECF DA neurochemistry, motor deficits, and functional recovery. Since ECF DA is recovered in the dorsal striatum despite a 95% depletion of tissue DA in this region, where does this DA come from? We will test hypotheses that ECF DA in dorsal striatum in recovered cats either originates in less denervated ventral striatal regions and via enhanced diffusion due to loss of DA reuptake sites reaches the dorsal striatum or that the dorsal striatal DA originates in endogenous terminals spared by the lesion or by a terminal sprouting response into the dorsal striatum. Quantitative autoradiographic studies of pre-and post-synaptic mechanisms in the striatum (i.i., DA reuptake sites/terminal density, DA D1 and D2 and serotonin 5-HT2 receptor densities) will provide additional information concerning the functional status of striatal sub-regions in normal, symptomatic, and recovered cats. This information, together with microdialysis data, should provide a more detailed understanding of functional striatal neurochemistry than previously obtained and should provide new information relevant to understanding the mechanisms underlying DA-related motor deficits and the nature of the ensuing recovery process. A second goal of the proposed research is study the functional role of DA in the striatum and its influence on sensorimotor integration and motor behavior by examining response properties of physiologically defined populations of striatal neurons during the performance of a learned motor response in normal, motor impaired, and motor recovered animals. Previous data suggests the attenuation of striatal sensory responsiveness during MPTP parkinsonism may be due to a disruption of sensory processing afferent to the striatum. This new hypothesis will be tested by examining sensory response properties of intralaminar thalamic neurons in normal, motor impaired, and recovered cats. These studies should provide new information concerning the possible mechanisms underlying sensorimotor impairment due to DA depletion and the nature of compensatory mechanisms which may lead to behavioral/motor recovery. These studies may have relevance for understanding pathophysiological mechanisms relevant to Parkinson's disease.
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