Chronic nicotine administration increases catecholamine release and biosynthesis in locus coeruleus (LC) neurons. Catecholamine biosynthesis is controlled by the activity of tyrosine hydroxylase (TH). In rats and mice, TH gene expression is up-regulated in the LC after daily repeated injections of nicotine for 14 days. This up-regulation of TH gene expression and the consequent increase in norepinephrine biosynthetic capacity in LC neurons may be one of the many changes that lead to physical dependence to nicotine. The experiments in this proposal are aimed at increasing our understanding of the mechanisms responsible for this up-regulation. The studies in this proposal test the following overall hypothesis: Repeated nicotine injections (twice per day) result in the repeated activation of LC neurons and consequent repeated enhanced release of norepinephrine (NE) in nerve terminal regions. These repeated responses lead to adaptive changes in the expression of specific genes, one of which is TH. In the LC, TH is induced via both transcriptional and post-transcriptional mechanisms in response to chronic nicotine. This proposal focuses on studying the post-transcriptional mechanisms.
The specific aims are: (1) To test whether the induction of TH mRNA in the LC in response to chronic nicotine treatment is mediated by increased TH mRNA stability or a sustained transcriptional response coupled to more efficient or alternative processing of TH RNA primary transcripts to the mature TH mRNA isoform(s). (2) To test whether polyC-binding protein (PCBP) isoforms are expressed in TH-positive neurons in the LC and whether chronic nicotine treatment induces PCBP. (3) To test whether PCBP and the polyC-rich sequence to which it binds in the 3' UTR of TH mRNA participate in the stabilization of TH mRNA in response to the activation of signaling pathways that mediate the response to nicotine. ? ? ?
| Radcliffe, Pheona M; Sterling, Carol R; Tank, A William (2009) Induction of tyrosine hydroxylase mRNA by nicotine in rat midbrain is inhibited by mifepristone. J Neurochem 109:1272-84 |
| Tank, A William; Xu, Lu; Chen, Xiqun et al. (2008) Post-transcriptional regulation of tyrosine hydroxylase expression in adrenal medulla and brain. Ann N Y Acad Sci 1148:238-48 |
| Chen, Xiqun; Rzhetskaya, Margarita; Kareva, Tatyana et al. (2008) Antiapoptotic and trophic effects of dominant-negative forms of dual leucine zipper kinase in dopamine neurons of the substantia nigra in vivo. J Neurosci 28:672-80 |
| Xu, Lu; Chen, Xiqun; Sun, Baoyong et al. (2007) Evidence for regulation of tyrosine hydroxylase mRNA translation by stress in rat adrenal medulla. Brain Res 1158:1-10 |
