Emergence of context-associated GluR1 and ERK phosphorylation in the nucleus accumbens core during withdrawal from cocaine self-administration

Reexposure to cocaine-associated environments promotes relapse to cocaine seeking and represents a persistent impediment to successful abstinence. Neurobiological adaptations are thought to underlie the preservation of drug-seeking behavior during protracted withdrawal periods, possibly including changes associated specifically with cocaine-paired contexts. We measured GluR(1)(S845) and extracellular signal-regulated kinase (ERK) phosphorylation in rat striatal subregions in an animal model of cocaine relapse. Animals with cocaine self-administration experience and their yoked partners were exposed to extinction conditions for one hour in the drug-paired environmental context after one day or three weeks withdrawal to measure protein phosphorylation induced by the cocaine-paired context in the absence of cocaine reinforcement. GluR(1)(S845) (an index of protein kinase A (PKA) activity) and ERK phosphorylation increased in the nucleus accumbens core of self-administering but not yoked animals after three weeks (but not one day) withdrawal, indicating a time-dependent emergence of context-associated protein phosphorylation in this accumbens subregion. In comparison, animals trained to self-administer sucrose displayed a similar increase in ERK, but not GluR(1)(S845), phosphorylation following reexposure to a sucrose-paired environment three weeks later, indicating that GluR(1)(S845) phosphorylation did not result solely from lever press behavior per se. In contrast, basal (home cage) GluR(1)(S845) phosphorylation was elevated in the nucleus accumbens shell and caudate-putamen after one day or three weeks cocaine withdrawal regardless of context exposure. These results suggest that time-dependent emergence of context-associated GluR(1)(S845) phosphorylation in the nucleus accumbens core may contribute to the persistence of cocaine-seeking behavior, whereas ERK phosphorylation may be a consequence of this behavior.