The time-course of monoamine and tyrosine hydroxylase depletion after single-dose administration of D-methamphetamine (40 mg/kg s.c.) was investigated in caudate-putamen of male Sprague-Dawley rats. Times evaluated were 6, 12, 48, 72 and 240 h following treatment. Tyrosine hydroxylase was significantly reduced by 29, 60, 66, 76 and 76% of control at each of the respective post-treatment time intervals. Dopamine was not reduced 6 h following treatment. Dopamine was significantly reduced by 53, 57, 68 and 74% 12, 48, 72 and 240 h post-treatment, respectively. Reductions in caudate-putamen serotonin began earlier and were ultimately larger than for dopamine, with significant reductions of 28, 33 55, 74 and 81% at each of the respective post-treatment intervals. Confirmation of neurotoxicity was provided by measurement of glial fibrillary acidic protein (GFAP) 240 h post-treatment. GFAP was increased at this time interval by 150% above control. Methamphetamine-induced hyperthermia during the 6 h immediately after treatment was comparable among the groups of animals used for analyses at each time interval. The results demonstrate that methamphetamine-induced monoamine reductions in the caudate-putamen occur rapidly, peak at 75-80% below controls, and last for at least 10 days after a single dose. These effects are as large or larger than those reported after the commonly used 10 mg/kgx4 dose treatment regimen administered at 2-h intervals and provides an alternate model for the investigation of methamphetamine-induced neurotoxicity.