DEVELOPMENT OF NIGROSTRIATAL NEURONAL SYSTEMS

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The objective of this research proposal is to elucidate the stages of ontogeny of dopamine and associated neuronal systems in the striatum and substantia nigra of the rat and to investigate the interactions between these neuronal systems during development. These studies will provide information on normal development of these systems and on the importance of interactions between these systems in regulating and controlling development. The major hypothesis of this study in that the interaction of neurotransmitters with their receptors during a specific time period in development is critical for the normal functional development of the receptors and of the postsynaptic neurons. This study will focus on the nigrostriatal dopamine pathway and on neurotransmitter systems known to interact with this pathway during development or in the adult rat. A major emphasis is the spatial, quantitative and functional development of neurotransmitter receptors. There are two major aspects to the proposal. First, basic studies on the development of neuronal systems will continue, with a concentration on neurotransmitter receptors and on functional markers for individual neuronal systems. The receptors of particular interest in this study are dopamine Dl and D2 and acetylcholine nicotinic and muscarinic receptors. Other markers for specific neuronal populations that will be examined include dopamine and DOPAC content, tyrosine hydroxylase activity, high-affinity choline uptake and choline acetyltransferase activity. The second aspect of the proposal involves use of procedures to perturb normal development, such an specific lesions or specific pharmacological agents, as a further means of examining the interaction of neuronal systems during development. The effects of these perturbations on the development of the particular neuronal systems will be used to investigate the importance of interactions between the various neuronal systems for each other's development. The proposed research utilizes autoradiography as a quantitative approach with very high resolution, together with biochemical pharmacological and molecular biology techniques to allow examination of the development of the anatomy and function of neurotransmitter systems and examination of the change induced in that development by alterations in the normal development of specific part of the system.