REGULATION OF TYROSINE-HYDROXYLASE PROMOTER ACTIVITY BY CHRONIC MORPHINE IN TH9.0-LACZ TRANSGENIC MICE

Levels of tyrosine hydroxylase (TH), the rate-limiting enzyme in catec holamine biosynthesis, are known to be upregulated in specific brain r egions by chronic administration of drugs of abuse. Chronic morphine a dministration increases TH levels in the locus coeruleus and ventral t egmental area, whereas chronic cocaine administration increases TH lev els in the ventral tegmental area only. While such upregulation of TH has been related to behavioral effects of the drugs, the mechanism und erlying these adaptations has remained controversial. To study the pos sibility 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 re porter gene, in transgenic mice. These TH9.0-LacZ mice have been shown to exhibit correct tissue-specific expression and regulation of the r eporter gene. We show here that chronic (but not acute) exposure of th e TH9.0-LacZ mice to morphine increases the expression of beta-galacto sidase (which is encoded by the LacZ gene) in the locus coeruleus by t wofold compared with sham-treated mice. In contrast, beta-galactosidas e expression in the ventral tegmental area was decreased 20-25% by chr onic morphine and unaffected by chronic cocaine administration. Simila r results were obtained after analysis of TH mRNA levels in these brai n regions by in situ hybridization. These results suggest that chronic morphine upregulates TH expression via transcriptional mechanisms in the locus coeruleus but by posttranscriptional mechanisms in the ventr al tegmental area.