The effects of an acute systemic injection of methamphetamine (mAMP) or cocaine (COC) on motor behavior (stereotypy, locomotor activity, and rearing) and extracellular dopamine (DA) in the ventral striatum were compared in Lewis (LEW) versus Fischer 344 (F344) rats, using in vivo microdialysis in awake freely moving animals. In addition, the behavioral response to repeated mAMP injections (i.e. sensitization) was characterized in LEW and F344 rats, as was the possibility of strain differences in drug pharmacokinetics. The major findings were: (i) LEW rats showed greater behavioral activation to an acute injection of both mAMP and COC, as indicated by a shift to the left in the dose-effect curves relative to F344 rats. (ii) LEW rats were more susceptible to mAMP sensitization. (iii) An acute injection of mAMP or COC enhanced the extracellular concentration of DA to a greater extent in LEW rats, as indicated by a significant shift to the left in the dose-effect curve relative to F344 rats. (iv) Strain differences in the behavioral and neurochemical effects of these drugs were characterized largely by differences in the duration of the drug response. (v) LEW rats had higher plasma and brain levels of mAMP and COC than F344 rats, suggesting that strain differences in pharmacokinetics may contribute to strain differences in the behavioral and neurochemical effects of these drugs.