Our goal is to determine the role of nicotinic receptor subtypes in the basal ganglia with the long-term objective of developing novel therapeutic strategies for Parkinson's disease. The rationale for this work is based on studies showing that nicotine administration improves locomotor deficits after a nigrostriatal lesion and, furthermore, that nicotine or smoking results in an apparent protective effect against nigrostriatal damage in rodents and in Parkinson's disease. However, multiple nicotinic receptors are activated by nicotine to result in beneficial but also side effects in both the peripheral and central nervous system. We hypothesize that specific nicotinic receptor populations in the brain are involved based on work demonstrating that the distinct subtypes have unique localization and molecular functions. We will approach these studies through four specific aims. As a crucial first step, we will identify the regional and cellular localization of nicotinic receptor subtypes in basal ganglia and determine the changes in receptor subtypes after nigrostriatal degeneration. This will be done using three different approaches including in situ hybridization, receptor autoradiography and immunocytochemistry and form the basis of Specific Aims 1 and 2. We will then initiate studies to assess the nicotinic receptor subtypes involved in striatal function as described in Specific Aim 3, followed by behavioral studies (Specific Aim 4) to determine the ability of nicotinic agonists to reverse parkinsonism. This work should increase our understanding of the role of different nicotinic receptor subtypes in basal ganglia function. ? ? In summary, the proposed work should provide new insight concerning alterations in nicotinic receptor subtypes after nigrostriatal damage and nicotinic agonist treatment. These data together with the results of the behavioral studies may form a basis for the use of nicotinic drugs in the treatment of Parkinson's disease. ? ?
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