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


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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    ABSTRACT: Decades of research confirm that noradrenergic locus coeruleus (LC) neurons are essential for arousal, attention, motivation, and stress responses. While most studies on LC transmission focused unsurprisingly on norepinephrine (NE), adrenergic signaling cannot account for all the consequences of LC activation. Galanin coexists with NE in the vast majority of LC neurons, yet the precise function of this neuropeptide has proved to be surprisingly elusive given our solid understanding of the LC system. To elucidate the contribution of galanin to LC physiology, here we briefly summarize the nature of stimuli that drive LC activity from a neuroanatomical perspective. We go on to describe the LC pathways in which galanin most likely exerts its effects on behavior, with a focus on addiction, depression, epilepsy, stress, and Alzheimer's disease. We propose a model in which LC-derived galanin has two distinct functions: as a neuromodulator, primarily acting via the galanin 1 receptor (GAL1), and as a trophic factor, primarily acting via galanin receptor 2 (GAL2). Finally, we discuss how the recent advances in neuropeptide detection, optogenetics and chemical genetics, and galanin receptor pharmacology can be harnessed to identify the roles of LC-derived galanin definitively.
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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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    ABSTRACT: The purpose of this study was to evaluate whether acupuncture stimulation attenuates withdrawal-induced behaviors in the rats during protracted abstinence following chronic morphine exposure. To do this, male rats were first exposed to morphine gradually from 20 to 100 mg/kg for 5 days, and subsequently naloxone was injected once to extend despair-related withdrawal behaviors for 4 weeks. Acupuncture stimulation was performed once at the SP6 (Sanyinjiao) acupoint on rat's; hind leg for 5 min during protracted abstinence from morphine. The acupuncture stimulation significantly decreased despair-like behavior deficits in the forced swimming test and low sociability in the open-field test as well as increased open-arm exploration in the elevated plus maze test in the last week of 4-week withdrawal period. Also the acupuncture stimulation significantly suppressed the increase in the hypothalamic corticotropin-releasing factor (CRF) expression, the decrease in the tyrosine hydroxylase expression in the locus coeruleus, and the decrease in the hippocampal brain-derived neurotrophic factor mRNA expression, induced by repeated injection of morphine. Taken together, these findings demonstrate that the acupuncture stimulation of SP6 significantly reduces withdrawal-induced behaviors, induced by repeated administration of morphine in rats, possibly through the modulation of hypothalamic CRF and the central noradrenergic system.
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    • "Decreasing Wnt secretion may potentially explain retraction, de-branching, and shrinking of dendrites following chronic morphine administration via depressed Wntinduced dendritogenesis (Hu, 2008; Liao, 2007; Franch-Marro, 2008). Alternatively, increased Wnt secretion may enable up-regulation of growth-related genes (McClung et al., 2005) or facilitate increased dendritogenesis enabling increased connections between afferents and LC dendrites such as under conditions of stress (Xu et al., 2004). Further studies are required to determine functional consequences of WLS trafficking. "
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    ABSTRACT: Opiate addiction is a devastating health problem, with approximately 2 million people currently addicted to heroin or non-medical prescription opiates in the United States alone. In neurons, adaptations in cell signaling cascades develop following opioid actions at the mu opioid receptor (MOR). A novel putative target for intervention involves interacting proteins that may regulate trafficking of MOR. Morphine has been shown to induce a re-distribution of a MOR-interacting protein Wntless (WLS, a transport molecule necessary for secretion of neurotrophic Wnt proteins), from cytoplasmic to membrane compartments in rat striatal neurons. Given its opiate-sensitivity and its well-characterized molecular and cellular adaptations to morphine exposure, we investigated the anatomical distribution of WLS and MOR in the rat locus coeruleus (LC)-norepinephrine (NE) system. Dual immunofluorescence microscopy was used to test the hypothesis that WLS is localized to noradrenergic neurons of the LC and that WLS and MOR co-exist in common LC somatodendritic processes, providing an anatomical substrate for their putative interactions. We also hypothesized that morphine would influence WLS distribution in the LC. Rats received saline, morphine or the opiate agonist [D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO), and tissue sections through the LC were processed for immunogold-silver detection of WLS and MOR. Statistical analysis showed a significant re-distribution of WLS to the plasma membrane following morphine treatment in addition to an increase in the proximity of gold-silver labels for MOR and WLS. Following DAMGO treatment, MOR and WLS were predominantly localized within the cytoplasmic compartment when compared to morphine and control. In a separate cohort of rats, brains were obtained from saline-treated or heroin self-administering male rats for pulldown co-immunoprecipitation studies. Results showed an increased association of WLS and MOR following heroin exposure. As the LC-NE system is important for cognition as well as decisions underlying substance abuse, adaptations in WLS trafficking and expression may play a role in modulating MOR function in the LC and contribute to the negative sequelae of opiate exposure on executive function.
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