Neuroadaptations affecting dopamine transmission within the prefrontal cortex and striatum are thought to underlie relapse to cocaine seeking after extended periods of abstinence. Regulator of G-protein signaling 4 (RGS4) is a forebrain-enriched protein known to be dynamically regulated by dopamine receptors in response to acute psychostimulant administration. In this report, chronic noncontingent (cocaine binge) or response-contingent (self-administration) delivery of cocaine followed by 2-3 weeks of abstinence resulted in a decrease of RGS4 mRNA in the dorsal striatum and prefrontal cortex. Furthermore, re-exposure to the cocaine-associated context after abstinence renewed the drug seeking and restored the levels of RGS4 mRNA to control values. Changes in RGS4 mRNA levels might signal abnormal receptor G-protein coupling that impacts cocaine seeking.