A role for the cyclic AMP systems in the development of morphine dependence has been previously reported. In this study we investigated whether morphine dependence was inhibited by phosphodiesterase (PDE) 4 inhibitors rolipram and diazepam. Dependence on morphine was induced by a 7-day s.c. implantation of morphine pellets. On day 8, morphine withdrawal was precipitated by an injection of naloxone. In order to determine the effect of rolipram and diazepam rats were injected with these drugs once daily for seven days as well as 30 min before of naloxone injection. When opioid withdrawal was precipitated, an enhanced noradrenaline turnover and increased level of cyclic AMP and cyclic GMP in the hypothalamic paraventricular nucleus (PVN) were observed 30 min after naloxone administration. Moreover, c-Fos expression was induced in the PVN after naloxone-precipitated morphine withdrawal. Co-administration of rolipram or diazepam with morphine during the pre-treatment period, significantly reduced the signs of withdrawal, the enhancement of noradrenaline turnover and the increase in cyclic AMP. However, these inhibitors did not modify either levels of cyclic GMP or c-Fos expression in the PVN. These findings demonstrate that co-administration of rolipram or diazepam with morphine attenuate the withdrawal syndrome and suggest that these compounds may prevent the up-regulation of the cyclic AMP pathway and the associated increase in cyclic AMP level in morphine-withdrawn rats.