The research plan porposes to study how diet influences the syntheses of two central nervous system (CNS) neurotransmitters, serotonin (5HT) and dopamine (DA). The biochemical/metabolic basis for the experiments is that food ingestion modifies the CNS uptake of tryptophan (TRP) and tyrosine (TYR), the amino acid precursors of 5HT and DA, and these changes then directly alter 5HT and DA synthesis. The TRP-5HT issues to be studied deal with characterizing the mechanisms by which diet influences CNS TRP uptake and 5HT synthesis. In particular, some experiments will define the dietary conditions that influence brain TRP level via changes in the plasma large neutral amino acid (LNAA) pattern, and thus the competitive transport of TRP into brain. Other studies will determine if brain TRP levels respond to dietary fat-induced changes in the albumin binding of TRP in blood, since there may be conditions under which unbinding TRP from albumin promotes CNS TRP uptake. Other experiments will explore for behavioral consequences of diet-induced changes in 5HT synthesis. In this proposal, sleep will be studied since sleep- waking behavior is linked in part to CNS 5HT neurons. The TYR- DA studies will define the dietary conditions under which CNS TYR levels and DA synthesis can be changed, the importance of phenylalanine (PHE) as a substrate and/or inhibitor of CNS DA synthesis and how diet influences CNS PHE levels and DA synthesis, and the importance of neuronal activation as a factor dictating which CNS subpopulations of DA neurons will and will not be sensitive to TYR-and PHE-induced changes in DA production. The general experimental design calls for animals to receive either a single meal, an injection of an amino acid, or a chronic diet. Thereafter, blood, brain and retinal samples will be obtained, and assayed for their contents of the LNAA (including TRP and TYR) and of 5HT, DA, and their precursors and metabolites. Measurements will be made using high-performance liquid chromatography coupled with fluorescence or electrochemical detection. Electroencephalographic sleep will be quantitated via recordings from cortical and hippocampal electrodes, and studied after rats have received different precursor and dietary treatments. When completed, the proposed studies should greatly enhance our understanding of the vulnerability of CNS 5HT and DA synthesis to precursor changes, and of the conditions under which the diet can influence the formation of these transmitters by altering TRP and TYR (and PHE) supply to the CNS.
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