Phosphorylation of GluR1, ERK, and CREB during spontaneous withdrawal from chronic heroin self-administration.

Negative motivational symptoms are observed soon after withdrawal from chronic opiate administration, and are thought to mediate dependence. Examination of brain region-specific signaling changes that accompany early withdrawal may shed light on neural mechanisms underlying negative reinforcement and dependence. Thus, we measured alterations in protein phosphorylation in multiple limbic brain regions in rats undergoing 24 h spontaneous or naltrexone-precipitated withdrawal from chronic (6 h/day) i.v. heroin self-administration. Region-specific increases in cyclic AMP-dependent GluR(1) (S845) 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-putamen. Increased GluR(1) (S845) phosphorylation was detected earlier (12 h withdrawal) in the central amygdala and ventral tegmental area. In contrast, prominent increases in extracellular signal-regulated 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-putamen but not in the nucleus accumbens. Naltrexone administration after 24 h withdrawal increased extracellular signal-regulated kinase phosphorylation in the central amygdala, and nucleus accumbens core and shell. Thus, spontaneous withdrawal from heroin self-administration produces region- and time-dependent changes in cyclic AMP and extracellular signal-regulated kinase activity that could contribute to the behavioral manifestation of opiate dependence.