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The Journal of Neuroscience, December 1, 1998, 18(23):9989-9995

Regulation of Tyrosine Hydroxylase Promoter Activity by Chronic Morphine in TH9.0-LacZ Transgenic Mice

Virginia A. Boundy¹, Stephen J. Gold¹, Chad J. Messer¹, Jingshan Chen¹, Jin H. Son², Tong H. Joh², and Eric J. Nestler¹

¹ Laboratory of Molecular Psychiatry, Departments of Psychiatry and Neurobiology, Yale University School of Medicine and Connecticut Mental Health Center, New Haven, Connecticut 06508, and ² Laboratory of Molecular Neurobiology, Cornell University Medical Center, White Plains, New York 10605

Levels of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, are known to be upregulated in specific brain regions by chronic administration of drugs of abuse. Chronic morphine administration increases TH levels in the locus coeruleus and ventral tegmental area, whereas chronic cocaine administration increases TH levels in the ventral tegmental area only. While such upregulation of TH has been related to behavioral effects of the drugs, the mechanism underlying these adaptations has remained controversial. To study the possibility that upregulation of TH occurs at the transcriptional level, we investigated the effect of chronic morphine or cocaine treatment on the activity of the TH gene promoter (9.0 kb), coupled to the LacZ reporter gene, in transgenic mice. These TH9.0-LacZ mice have been shown to exhibit correct tissue-specific expression and regulation of the reporter gene. We show here that chronic (but not acute) exposure of the TH9.0-LacZ mice to morphine increases the expression of -galactosidase (which is encoded by the LacZ gene) in the locus coeruleus by twofold compared with sham-treated mice. In contrast, -galactosidase expression in the ventral tegmental area was decreased 20-25% by chronic morphine and unaffected by chronic cocaine administration. Similar results were obtained after analysis of TH mRNA levels in these brain regions by in situ hybridization. These results suggest that chronic morphine upregulates TH expression via transcriptional mechanisms in the locus coeruleus but by post-transcriptional mechanisms in the ventral tegmental area.

Key words: opiate dependence; cocaine; locus coeruleus; ventral tegmental area; in situ hybridization; transcriptional regulation; catecholamines

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18239989-07$05.00/0

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