STIMULATION OF TYROSINE-HYDROXYLASE GENE-TRANSCRIPTION RATE BY NICOTINE IN RAT ADRENAL-MEDULLA

The administration of nicotine stimulates the transcription rate of the tyrosine hydroxylase gene in rat adrenal medulla. This stimulation occurs very rapidly (within 10 min) after the subcutaneous injection of nicotine and persists for at least 1 hr after a single injection of the drug. Repeated injections of the drug (seven injections once every 30 min) are associated with a more persistent activation of the gene (for at least 3 hr) and elicit the induction of tyrosine hydroxylase mRNA and tyrosine hydroxylase protein. Quantitatively, the increases in tyrosine hydroxylase gene transcription rate, mRNA, and protein are approximately equivalent. The effect of nicotine is dose dependent; a significant increase in tyrosine hydroxylase gene transcription rate is observed using 1.0 mg/kg nicotine, whereas 0.33 mg/kg nicotine produces no effect. The nicotinic receptor antagonists hexamethonium and mecamylamine partially inhibit the nicotine-mediated stimulation of the tyrosine hydroxylase gene. The lack of total blockade of the nicotine-mediated effect suggests that nicotine acting centrally may elicit the release of substances from the splanchnic nerve, that interact with receptors (other than the nicotinic receptor) that play a role in regulating the tyrosine hydroxylase gene. The administration of carbachol also stimulates rat adrenomedullary tyrosine hydroxylase gene transcription rate. The effect of carbachol is not inhibited by hexamethonium but is completely blocked by the muscarinic antagonist atropine. The muscarinic agonist bethanechol also stimulates this gene in rat adrenal medulla. Our results suggest that multiple receptors and signal transduction pathways are involved in the regulation of the tyrosine hydroxylase gene in the rat adrenal medulla.