Tetrahydrobiopterin is the essential cofactor for tyrosine and tryptophan hydroxylases, the rate-limiting enzymes in the biosynthesis of the monoamine neurotransmitters. Recent evidence also suggests roles for tetrahydrobiopterin in cell proliferation and differentiation. There is unequivocal evidence of inherited deficiencies in human monoamine neurotransmission which are the direct result of genetic defects in tetrahydrobiopterin metabolism. There is suggestive evidence that these genetic defects might also result in abnormal neural development. This competitive renewal outlines a broad series of experiments performed both in culture and in vivo which are designed to further the understanding of the role(s) of tetrahydrobiopterin in the regulation of catecholamine biosynthesis and the development and plasticity of the catecholamine neuron phenotype. Since it is now apparent that there are important differences in the metabolism of tetrahydrobiopterin across specific populations of catecholamine neurons, this objective can only be accomplished by first obtaining a more complete understanding of the nature of these differences. The regulation of cofactor metabolism will thus be studied in dopamine and norepinephrine-containing neurons from the central and peripheral nervous systems maintained in primary tissue culture. The short and long-term interaction between tetrahydrobiopterin and catecholamine biosynthetic systems will be investigated using tissue culture and intact animals with the expectation that these biosynthetic systems are coordinately regulated. The developmental expression and plasticity of the tetrahydrobiopterin phenotype as it relates to catecholamine neurons will also be investigated in tissue culture and in the intact animal. These goals are related in that the interpretation of the interaction between catecholamine and cofactor biosynthetic systems during development and in response to neurotransmitter plasticity will be highly dependent upon the further characterization of their interaction in the mature neuron. It is hoped that these studies will ultimately aid in a better understanding of the etiology of neuropsychiatric disorders and provide different directions for therapeutic approaches in its treatment.
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