Studies indicate that the neurotransmitter dopamine (DA) interacts with the enkephalin (ENK, e.g. Met5-enkephalin) and tachykinin (TAK, e.g. substance P) containing peptidergic neurons of the basal ganglia. For example, DA receptor blockade or lesion of nigrostriatal DA neurons leads to enhance ENK and decreased TAK concentrations in the basal ganglia and/or substantia nigra. However, the precise nature of development and long-term plasticity in these peptidergic systems during DA deficiency is unclear, partly because of the paucity of information concerning their biosynthetic processes (e.g. transcription, translation and peptide formation). An elucidation of DA-ENK/TAK relationship is important, since a deficiency of DA is implicated to the movement disorders associated with Parkinsonism and Lesch- Nyhan disease. The working hypothesis is that the development and maintenance of peptide biosynthesis in the striatopallidal ENK and striatonigral TAK neurons is under a regulatory control of nigrostriatal DA and that events that alter the activity of DA neurons will also modify the biosynthesis. The neurotoxin, 6- hydroxydopamine induced DA deficiency in rat during an early postnatal period will be used as a model to study DA-ENK/TAK relationship. The status of the peptidergic neurons will be assessed in terms of the rate of transcription of preproenkephalin and preprotachykinin genes by transcription run-on assays, the abundance of specific mRNAs by molecular hybridization, the concentrations of certain precursor and peptides by radioimmunoassays. DA, 5-hydroxytryptamine and their metabolites will also be assayed. This proposal will address the following specific questions: a) What are the molecular events involved in the postnatal development and biosynthesis of ENK and TAK peptides? b) Does neonatally induced DA deficiency lead to enhanced ENK and retarded TAK biosynthesis; if so, at what period in development does this occur? c) Will replenishment of the deficit transmitter DA, or treatment with selective DA receptor (D1 or D2) agonists or peptide (TAK) or opioid antagonist at the appropriate development period reverse or modify the peptidergic and certain behavioral alterations associated with DA deficiency? d) How does the destruction of serotonergic terminals which are known to proliferate in the striatum following neonatal DA deficiency affect the peptidergic neurons? The results obtained will be highly relevant to further understanding of neurobiologic basis of basal ganglia function.
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