Article

McClung CA, Nestler EJ, Zachariou V. Regulation of gene expression by chronic morphine and morphine withdrawal in the locus ceruleus and ventral tegmental area. J Neurosci 25: 6005-6015

Department of Psychiatry and Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2005; 25(25):6005-15. DOI: 10.1523/JNEUROSCI.0062-05.2005
Source: PubMed

ABSTRACT

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.

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    • "Several lines of converging evidence suggest that LCderived galanin is at least partially responsible for some of these phenotypes. First, chronic opiate exposure and withdrawal increases galanin and galanin receptor expression in the LC, and withdrawal-induced LC activity is decreased by galanin (Georgescu et al., 2003;Holmes et al., 2012;McClung et al., 2005;Zachariou et al., 1999Zachariou et al., , 2000). Second, given the suppression of LC firing produced by autocrine release of galanin discussed earlier, one might predict that NE depletion would phenocopy increased galanin transmission; indeed, this is the case in many instances. "
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    • "Many studies have shown that CRF levels are correlated with anxiety in animal models of depression, suggesting a possible link between high level expression of CRF and predisposition to anxiety or morphine withdrawal-induced depression [30]. In addition, previous studies suggested that morphine dependence and withdrawal induce hyperactivity of noradrenergic pathways and an increase in TH modulation in the LC [31]. It has been proposed that clinical anxiety or depression may be the result of alterations in the activity of the LC in central noradrenergic system [32]. "
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    • "Further, the ability to maintain or restore redox homeostasis might include underlying changes in gene expression mediated via epigeneticmodulation of gene transcription in response to various stimuli, including drugs of abuse (Mao et al., 2002; Xu et al., 2003; McClung et al., 2005; Christie, 2008; Robison and Nestler, 2011; Schwarz et al., 2011). However, we propose that an absence of these stimuli can render the adaptive changes excessive, leading to a plethora of compensatory mechanisms which could potentially result in a switched homeostasis in the opposite direction (Xu et al., 2003Xu et al., , 2006 McClung et al., 2005). Thus, redox-responsive adaptive regulation of epigenetic status might exhibit opposite changes during sustained drug exposure vs. drug withdrawal states and contribute to the observed symptoms (Figure 3). "
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