Depletion of brain dopamine (DA) in rats produces a syndrome of aphagia, adipsia, bradykinesia, and profound sensorimotor neglect. This bradykinesia and sensorimotor neglect is not due to a primary sensory or motor deficit, but has been characterized as a deficit in sensory-motor integration. These symptoms are very similar to those seen in Parkinson's Disease, which is thought to be due to a loss of DA-containing neurons in the substantia nigra. Although rats with bilateral DA depletion have provided many insights into the function of brain DA neurons, they are difficult to maintain, requiring extensive post-operative care. However, rats with unilateral nigrostriatal DA depletion have provided a very useful animal model of Parkinson's Disease. These animals neglect stimuli presented to the contralateral body surface or space, and when treated with DA-mimetic drugs display a highly quantifiable behavioral asymmetry known as rotational (circling) behavior. Recently, it has been shown that grafts of fetal substantia nigra or adrenal medulla tissue placed in or near the denervated striatum can at least partially reverse these behavioral asymmetries. The evidence available to date suggests that these grafts alleviate the symptoms of DA depletion by releasing catecholamines, but this hypothesis has never been directly tested. In this application we propose a series of experiments to do so. In the first series of experiments we propose to develop a push-pull perfusion technique to measure the efflux of catecholamine metabolites into the lateral ventricle as an index of catecholamine release. Next, we will compare the ability of fetal substantia nigra, adrenal medulla or fetal tectal tissue grafts placed into the lateral ventricle to release catecholamines and/or catecholamine metabolites into the lateral ventricle, over time following the transplant. Thirdly, we will use a series of pharmacological manipulations to determine: (1) if there is any relation between the ability of catecholamine-rich tissue grafts to release catecholamines and their ability to attenuate the rotational behavior imbalance produced by unilateral DA depletion; and (2) whether any of the normal mechanisms governing catecholamine release are operative in tissue grafts.
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