Quantitative in situ hybridization histochemistry was used to compare the effects of AMPH administration on mRNAs coding for zif/268, a member of the zinc finger family of immediate early genes, and the opioid peptides, preprodynorphin (PPD) and preproenkephalin (PPE), in rat striatum after 3 dosing schedules: (1) acute; (2) once a day for 5 days, and (3) once a day for 5 days followed 10 days later by a challenge dose. Behavioral ratings indicated that the activity of rats was significantly higher after 5 daily AMPH (5 mg/kg, i.p.) injections than after a single 5 mg/kg injection and that the activity of AMPH-pretreated rats was significantly higher than that of saline-pretreated rats after a 1 mg/kg challenge dose 10 days later. Three hours after acute administration of AMPH to naive rats, PPD mRNA expression in the dorsal (caudatoputamen) and ventral (nucleus accumbens, NAc) striatum as well as PPE and zif/268 mRNA expression in the dorsal, but not ventral, striatum were increased as compared to saline-treated rats. Five daily treatments with AMPH augmented acute AMPH-induced increases in PPD mRNA expression in the caudatoputamen but not in the NAc. The increase in striatal zif/268 mRNA expression induced by acute AMPH was, in contrast, reduced after 5 daily treatments with AMPH. AMPH induced PPE expression to the same extent in rats treated with one or 5 daily injections. Hybridization performed 3 h after AMPH challenge in AMPH-pretreated rats failed to demonstrate augmentation of AMPH-stimulated zif/268, PPD, or PPE mRNA expression in the striatum as compared to saline-pretreated rats. These results indicate that an augmented response of PPD and a decreased response of zif/268 mRNA expression in striatal neurons are closely associated with the initiation of behavioral sensitization induced by repeated, intermittent AMPH treatments. In contrast, a clear dissociation exists between the expression of sensitized behaviors and unsensitized zif/268, PPD and PPE mRNA in the striatum in response to a challenge dose of AMPH. Possible functional implications of these alterations in the initiation and expression of AMPH-induced behavioral sensitization are discussed.