The dose-related effects of a single injection of D-amphetamine (AMPH) or methamphetamine (METH) on the mRNA expression of the immediate early gene zif/268 and the opioid peptide preprodynorphin, in rat forebrain, were investigated with quantitative in situ hybridization histochemistry 3 h after injection. Both drugs at equimolar doses (3.75, 7.5, 15 and 30 mumol/kg) up-regulated zif/268 mRNA expression in cerebral cortex in a dose-dependent fashion. In the "nose" area of the sensory cortex, all doses of METH, but not AMPH, induced a substantial, dose-dependent increase in zif/268 mRNA. Dose-dependent induction of zif/268 mRNA also occurred in caudoputamen after injection of AMPH at all doses. However, dose-dependent increases in zif/268 mRNA in caudoputamen in METH-treated rats and in nucleus accumbens in AMPH-treated and METH-treated rats were seen only after the three lower doses. Injection of 30 mumol/kg actually decreased zif/268 mRNA induction in these areas to or below that detected after 3.75 mumol/kg. Preprodynorphin mRNA expression in the striatum was dose-dependently increased by either drug at all doses. These results demonstrate a clear dose-related responsiveness of zif/268 and preprodynorphin gene expression in cortical and/or striatal neurons that is positively correlated with a dose-dependent motor-stimulating effect of AMPH and METH. METH is a more potent psychostimulant than AMPH in eliciting behavioral and genomic activity at equimolar doses, and METH elicits a qualitatively different pattern of genomic activity in some forebrain regions, especially in the higher dose range.