BIOSYNTHESIS OF NEUROTRANSMITTERS IN THE CNS

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During the proposed award period, the applicant will continue his research along two, ongoing lines of investigation in his lab, the first on the role of precursor availability in controlling the synthesis and release of monoamine neurotransmitters in the central nervous system (CNS), and the second on the factors governing the synthesis in brain of the somatostatin (SRIF) family of neuropeptides. In the first set of projects, the applicant will continue to study how diet influences the syntheses of serotonin (5HT) and dopamine (DA), which derive from tryptophan (TRP) and tyrosine (TYR), respectively. The TRP-5HT issues to be studied will be (a) to characterized how diets of different composition influence CNS TRP uptake and 5HR synthesis, and (b) to explore for behavioral effects of diet-induced changes in 5HT synthesis, in this case on sleep. the TYR-DA studies will define the dietary conditions under which CNS TYR levels and DA synthesis can be changed, and the role of phenylalanine as a substrate for and/or inhibitor of TYR hydroxylase in vivo. In the second set of projects, the applicant will continue his studies of factors that influence in vivo SRIF biosynthesis in hypothalamus and cerebral cortex, using an in vivo radioactive labeling method to estimate SRIF synthesis. The proposal is to continue investigating the effects on SRIF synthesis of growth hormone (GH), the SRIF molecules themselves, and GH releasing hormone, administered either systemically or into the CNS. IN addition, effects of neuropharmacologic agents and of stress and fasting will also be studied, because they influence GH secretion via an action on hypothalamic SRIF. The broad goal is to identify the control point(s) in the SRIF pathway and to determine under what situations, both physiologic and pharmacologic, SRIF synthesis is manipulated via these controls. Both hypothalamus and cerebral cortex will be examined. Hypothalamic SRIF peptides have neuroendocrine functions, while cortical SRIF peptides serve neurotransmitter/neuromodulator roles. The controls governing SRIF synthesis in hypothalamus and cortex may thus be different, and elucidation of such differences may help to understand more generally how the SRIF pathway is controlled. The amino acid-monoamine work, when completed, should greatly enhance our understanding of the vulnerability of CNS 5HT and DA synthesis to precursor changes. The SRIF results should illuminate the types of controls of an important neuropeptide biosynthetic pathway in brain, and improve understanding of the functional role of SRIF neurons in regulating GH secretion.