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Objective Several lines of evidence have suggested a critical role for CREB activities, which activated by changes of cAMP in mediating the rewarding and reinforcement effects of many drugs of abuse.Inhibitors of phosphodiesterase (PDE) increase the concentration of cAMP and activate the CREB.Rolipram, a cAMP-selective phosphodiesterase 4 (PDE4) inhibitor has been thought to enhance the cognitive function, but whether the rolipram inhibit the drug seeking behavior is still unclear.Methods Our aim was to investigate the effect of rolipram, on cueor heroin-primed heroin-seeking in rats.Rats were self-administered heroin for 12 days and extinguished for 12 days, then, conditioned cues or heroin priming (250 μg/kg) was introduced for the reinstatement of heroin-seeking behaviors.Results The reinstatement of heroin seeking induced by cues or heroin priming was attenuated by administration of rolipram (0, 0.3, 1 or 3 mg/kg, i.p.) in a dose-dependent manner.The pretreatment with rolipram did not inhibit the heroin self-administration.The expression of p-CREB in nucleus accumbens was increased when pretreatment with rolipram.Conclusion The data suggested that rolipram could be used as a potential pharmacotherapeutic agent to reduce drug-seeking.