Behavioural effects of psychostimulant and opiate drugs are mediated in part by cAMP pathways operating in the nucleus accumbens. Degradation of cAMP occurs through the action of phosphodiesterases, such as the Type IV phosphodiesterases (PDE4s) that are found throughout the brain. To examine the potential role of PDE4 in reward-mediated behaviour, we measured the effects of rolipram, a PDE4 selective inhibitor, on cocaine (18 mg/kg i.p.) and morphine (5 mg/kg s.c.) conditioned place preference in Swiss Webster mice. Rolipram (0, 0.2 or 1.0 mg/kg i.p.) given 30 min prior to drug administration dose-dependently reduced conditioning due to both cocaine and morphine. However, rolipram did not affect place preference induced by food, nor did it prevent the expression of a previously established place preference conditioned by cocaine or morphine. In a second experiment, rolipram administered 30 min prior to a single cocaine injection (50 mg/kg i.p.), did not alter cocaine-induced c-Fos expression in the caudate putamen or nucleus accumbens core. However, rolipram, but not cocaine, induced c-Fos in the nucleus accumbens shell. These results indicate that elevation of cAMP in neurons that express PDE4s may attenuate the rewarding properties of cocaine and morphine, but does not alter the cocaine signalling cascade that induces c-Fos expression. Thus, PDE4-mediated regulation of cAMP levels could underlie the establishment of reward valence to abused drugs.