Emergence of context-associated GluR ₁ 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.