The objective of this research proposal is to elucidate the stages of the ontogeny of dopaminergic and associated neuronal systems in the striatum and substantia nigra of the rat and to investigate the interactions between these neuronal systems during development. This will provide information on the role of these interactions in regulating and controlling neuronal development. This study will focus on the nigrostriatal dopaminergic pathway and on neuronal systems known to interact with this pathway in development or in the adult rat. There are two aspects to the proposal. First, basic studies on the development of neuronal systems will be done, concentrating on neurotransmitter receptors as markers for development of individual neuronal systems. The receptors of particular interest are dopamine D1 and D2, serotonin S2, cholinergic muscarinic, opiatergic mu and neurotensin receptors. Other markers will also be examined, including dopamine content, high-affinity choline uptake and enkephalin levels. Second, procedures will be used to perturb normal development of particular parts of the system. The effects of these perturbations on the development of other neuronal systems will be examined to investigate the importance of interactions between the neuronal systems for each other's development. The proposed research utilizes quantitative light microscopic autoradiography combined with biochemical pharmacological techniques as an approach that allows examination of the normal development of neurotransmitter systems and examination of the changes induced in that development by interference with normal neuronal interactions in a quantitative manner at very high resolution. This will, in turn, provide a basis for further studies on the effects of xenobiotic agents, such as drugs or environmental pollutants, on the development of the central nervous system.
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