Effects of an interaction between rolipram, a cyclic adenosine 3', 5'-monophosphate (cyclic AMP) phosphodiesterase inhibitor, and methamphetamine on the development of behavioral sensitization were observed in rats. In vivo microdialysis showed that a single dose of 4 mg/kg methamphetamine (i.p.) significantly increased striatal dopamine levels while coadministration with 4 mg/kg rolipram (i.p.) did not affect these levels. Also, methamphetamine alone did not alter striatal cyclic AMP levels but coadministration with rolipram and rolipram alone significantly increased these levels. The administration of 4 mg/kg methamphetamine (i.p.) once a day for 5 days significantly enhanced hyperlocomotion and rearing induced by a 2-mg/kg methamphetamine challenge (i.p.) after a 1-week withdrawal period, compared with controls or coadministration with 4 mg/kg rolipram (i.p.). Striatal dopamine levels, detected by in vivo microdialysis, were increased following the challenge but were comparable between the groups. These findings suggest that rolipram prevents methamphetamine-induced behavioral sensitization by increasing cyclic AMP levels while not affecting dopamine-releasing processes.