Second messenger and protein phosphorylation mechanisms underlying opiate addiction: Studies in the rat locus coeruleus |
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Authors: | Xavier Guitart Eric J Nestler |
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Institution: | (1) Laboratory of Molecular Psychiatry, Departments of Psychiatry and Pharmacology, Yale University School of Medicine and Connecticut Mental Health Center, 34 Park Street, 06508 New Haven, CT |
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Abstract: | We have studied the role of second messenger and protein phosphorylation pathways in mediating changes in neuronal function associated with opiate addiction in the rat locus coeruleus. We have found that chronic opiates increase levels of the G-protein subunits Gi and Go , adenylate cyclase, cyclic AMP-dependent protein kinase, and a number of phosphoproteins (including tyrosine hydroxylase) in this brain region. Electrophysiological data have provided direct support for the view that this up-regulation of the cyclic AMP system contributes to opiate tolerance, dependence, and withdrawal exhibited by these neurons. As the adaptations in G-proteins and the cyclic AMP system appear to occur at least in part at the level of gene expression, current efforts are aimed at identifying the mechanisms, at the molecular level, by which opiates regulate the expression of these intracellular messenger proteins in the locus coeruleus. These studies will lead to an improved understanding of the biochemical basis of opiate addiction.Special issue dedicated to Dr. Paul Greengard |
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Keywords: | Opiate tolerance dependence and withdrawal opiate addiction locus coeruleus G-proteins cyclic AMP cyclic AMP-dependent protein kinase protein phosphorylation CREB Fos regulation of neuronal gene expression |
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