Relapse to cocaine-seeking increases activity-regulated gene expression differentially in the striatum and cerebral cortex of rats following short or long periods of abstinence

One of the most insidious features of cocaine addiction is a high rate of relapse even after extended periods of abstinence. A wide variety of drug-associated stimuli, including the context in which a drug is taken, can gain incentive motivational properties that trigger drug desire and relapse to drug-seeking. Both animal and clinical studies suggest that extensive cocaine exposure may induce a transition from cortical to striatal control over decision-making as compulsive drug-seeking emerges. Using an animal model of relapse to cocaine-seeking, the present study investigated the expression patterns of three different activity-related genes (c-fos, zif/268, and arc) in cortical and striatal brain regions implicated in compulsive drug-seeking in order to determine the neuroadaptations that occur during context-induced relapse following brief or prolonged abstinence from cocaine self-administration. Re-exposure to the environment previously associated with cocaine self-administration following 22 h or 15 days of abstinence produced a significant increase in zif/268 and arc, but not c-fos mRNA, in the caudate-putamen and nucleus accumbens. With the exception of arc mRNA levels following 15 days of abstinence, all three genes were increased in the anterior cingulate cortex of animals with a cocaine history when they were re-exposed to the operant chamber. Additionally, c-fos, zif/268, and arc expression was differentially affected in the motor and sensory cortices at both timepoints. Together, these results support convergent evidence that drug-seeking induced by a cocaine-paired context changes the activity of corticostriatal circuits.