Regulation of gene expression by chronic morphine and morphine withdrawal in the locus ceruleus and ventral tegmental area.
Morphine dependence is associated with long-term adaptive changes in the brain that involve gene expression. Different behavioral effects of morphine are mediated by different brain regions, for example, the locus ceruleus (LC), a noradrenergic nucleus, is implicated in physical dependence and withdrawal, whereas the ventral tegmental area (VTA), a dopaminergic nucleus, contributes to rewarding and locomotor responses to the drug. However, the global changes in gene expression that occur in these brain regions after morphine exposure and during withdrawal remain unknown. Using DNA microarray analysis in both mice and rats, we now characterize gene expression changes that occur in these brain regions with chronic morphine and antagonist-precipitated withdrawal. In the LC, numerous genes display common regulation between mouse and rat, including tyrosine hydroxylase, prodynorphin, and galanin. Furthermore, we identify clusters of genes that are regulated similarly by chronic morphine and by withdrawal, as well as clusters that show opposite regulation under these two conditions. Interestingly, most gene expression changes that occur in the VTA in response to chronic morphine are different from those seen in the LC, but the gene expression patterns in the two brain regions are very similar after withdrawal. In addition, we examined two genes (prodynorphin and FK506 binding protein 5) that are strongly regulated by chronic morphine or morphine withdrawal in the LC for their role in regulating withdrawal-associated behaviors. Inhibition of either protein profoundly affects withdrawal responses, demonstrating that the genes identified in this study have important functional roles in mediating opiate-induced behaviors.