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Thus, we measured alterations in protein phosphorylation in multiple limbic brain regions in rats undergoing 24 h spontaneous or naltrexone\u2010precipitated withdrawal from chronic (6 h\/day) i.v. heroin self\u2010administration. Region\u2010specific increases in cyclic AMP\u2010dependent GluR<jats:sub>1<\/jats:sub><jats:sup>S845<\/jats:sup>phosphorylation were found in the nucleus accumbens shell, basolateral amygdala, hippocampal CA1 and CA3 subregions, and premotor cortex from 12 to 24 h of spontaneous withdrawal, and there were no changes in prefrontal cortex, nucleus accumbens core or caudate\u2010putamen. Increased GluR<jats:sub>1<\/jats:sub><jats:sup>S845<\/jats:sup>phosphorylation was detected earlier (12 h withdrawal) in the central amygdala and ventral tegmental area. In contrast, prominent increases in extracellular signal\u2010regulated kinase phosphorylation were found in both prefrontal and premotor cortex, and CA1 and CA3 between 12 and 24 h withdrawal. Phosphorylation of striatal cyclic AMP response element binding protein increased in the caudate\u2010putamen but not in the nucleus accumbens. Naltrexone administration after 24 h withdrawal increased extracellular signal\u2010regulated kinase phosphorylation in the central amygdala, and nucleus accumbens core and shell. Thus, spontaneous withdrawal from heroin self\u2010administration produces region\u2010 and time\u2010dependent changes in cyclic AMP and extracellular signal\u2010regulated kinase activity that could contribute to the behavioral manifestation of opiate dependence. Synapse 63:224\u2013235, 2009. \u00a9 2008 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/syn.20601","type":"journal-article","created":{"date-parts":[[2008,12,17]],"date-time":"2008-12-17T11:10:01Z","timestamp":1229512201000},"page":"224-235","source":"Crossref","is-referenced-by-count":40,"title":["Phosphorylation of GluR1, ERK, and CREB during spontaneous withdrawal from chronic heroin self\u2010administration"],"prefix":"10.1002","volume":"63","author":[{"given":"Scott","family":"Edwards","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danielle L.","family":"Graham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimberly N.","family":"Whisler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David 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