We have assessed the time course of repeated administration of methamphetamine (METH; 4 mg/kg) and withdrawal on the levels of preprotachykinin (PPT) and preproenkephalin (PPE) mRNA abundance in the caudate-putamen (CPu) and nucleus accumbens (NAc) of the rat brain by in situ hybridization histochemistry. Neostriatal PPT mRNA levels rose gradually between days 1 and 6 of treatment, with the greatest elevation observed at day 6. After 6 days of daily injections twice per day, PPT mRNA increases in dorsomedial (172%) and ventromedial (196%) aspects of the CPu were significantly higher than in dorsolateral (147%) and ventrolateral (135%) subdivisions. Similarly, PPT mRNA levels were increased in the anterior CPu (163%) and NAc (121%). Concurrent administration of METH and the NMDA receptor antagonist MK-801 attenuated METH-induced increases of PPT mRNA in all aspects of the CPu at day 6 of treatment and completely prevented the increase in the NAc. Moreover, animals treated with METH for 6 days and then withdrawn for 15 days displayed PPT mRNA levels in striatum and accumbens that were statistically indistinguishable from those of controls. Adjacent sections from the same brains were used to assess PPE mRNA levels. PPE mRNA levels were transiently elevated in dorsal and ventral aspects of the CPu at day 1 and decayed to control levels at days 3 and 6. The results demonstrate that progressive treatment with methamphetamine causes stepwise elevation of preprotachykinin mRNA levels in the neostriatum. Moreover, the increase of neuropeptide mRNA shows selectivity, since PPE mRNA levels did not display progressive accumulation of message. The effects of progressive METH treatment on neostriatal PPT mRNA expression decay when the drug is withdrawn, suggesting that this neuropeptidergic system may not represent a neuroadaptation sustaining enduring sensitization to amphetamines, but may play a role in the progressive augmentation of locomotor activity elicited by this class of drug.