This is the first revision of a competing renewal that received a score of 189 (29.8) from an associate professor at the University of Rochester, who has been studying tyrosine hydroxylase for many years. His research has principally concentrated on stress interactions, but he is now interested in investigating the complexities of nicotine effects on expression of this regulatory enzyme in catecholamine synthesis. Nicotine increases catecholamine release and biosynthesis in the adrenal medulla and in the brain. The effects on the adrenal medulla likely mediate nicotine's peripheral actions, e.g. on the cardiovascular system. However, brain effects on catecholaminergic systems might mediate some of nicotine's addictive properties. Tyrosine hydroxylase (TH) gene expression is enhanced in both the adrenal medulla and the locus coeruleus (LC) after twice daily injections of nicotine for 14 days; a single injection does not induce TH. Repeated nicotine injections result in repeated activation of several signaling pathways in catecholaminergic cells. Nicotinic antagonists do not completely block induction of TH by nicotine, suggesting that the induction may involve transsynaptic signaling pathways. Further, the induction of TH gene expression is hypothesized to involve both transcriptional and post-transcriptional mechanisms. The investigator will use two animal models (rat and transgenic mouse) and a tissue culture system (PC12 cells, a rat pheochromocytoma)to 1)Test whether the enhanced induction of TH gene expression observed after repeated nicotine treatment is mediated by transcriptional and/or post-transcriptional mechanisms; 2) Test which adrenal chromaffin cell receptors participate in the enhanced induction of TH gene expression which occurs after repeated nicotine administration; and 3) Test the hypothesis that the enhanced induction of TH in the LC is due to repeated stimulation of intracellular signaling pathways. by active nAChRs.
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