The effects of neurotoxic doses of methamphetamine on basal and evoked overflow of dopamine in the striatum were examined in awake rats using microdialysis. Male Fischer-344 rats were administered methamphetamine (5 mg/kg s.c.) or saline four times in 1 day at 2-h intervals. Microdialysis experiments were carried out 1 week later. Basal levels of dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid were reduced in the striatum of the methamphetamine-treated animals. Local application of excess potassium (100 mM) and amphetamine (100 microM), and intraperitoneal injection of amphetamine (1.5 mg/ kg), led to increased levels of extracellular dopamine in the striatum of both methamphetamine- and saline-treated rats. However, the increase was significantly less in the methamphetamine-treated animals. Tissue levels of dopamine and metabolites were reduced in the striata of rats treated with methamphetamine. These results indicate that treatment with neurotoxic doses of methamphetamine can lead to functional changes in dopamine release in the striatum of Fischer-344 rats.