There are numerous lines of evidence suggesting an intimate relationship between certain endogenous neurotransmitters and adaptive or maladaptive behavior in many animals, including man. The catecholamines have received attention in this regard. However, despite extensive investigation, knowledge regarding the relationships between catecholamines and behavior have been compromised by a lack of detailed information concerning mechanisms regulating their metabolism. The primary objective of our research program is to elucidate the toles of genetic and environmental variables that interact in regulating the catecholamine biosynthesizing enzymes tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH) and phenylethanolamine-N-methyltransferase (PNMT). Our program focuses on 2 particular areas. (1) Regulation of Serum DBH Activity. Our working hypothesis is that serum DBH is a trait-dependent variable subject to relatively few state-dependent changes. We feel that disposal pathways, presumably located in the liver, are primary determinants of serum DBH activity and may be intimately related to both inherited and acquired differences in circulating enzyme activity. The major objective of the rat studies is to define the metabolic systems regulating serum DBH. The clinical objective will be to evaluate the reported association between low serum DBH activity and liability to schizophrenia within well-studied pedigrees. The rat studies will provide the necessary mechanistic framework for interpreting the biological implications of the clinical data. (2) Regulation of Adrenal Enzymes. Our working hypothesis is that mechanisms regulating enzyme responses to stress are inherited. We will determine whether defined pituitary-dependent and neuronally-dependent processes controlling TH and DBH responses to stress are independent of those controlling PNMT responses. The specific mechanisms underlying the responses also will be assessed. These studies will provide valuable insights into the role of inherited factors that regulate metabolic functions essential to physiologic and behavorial adaptation.
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