Methamphetamine is a widely abused illicit drug. Recent epidemiological studies showed that methamphetamine increases the risk for developing Parkinson's disease in agreement with animals studies showing dopaminergic neurotoxicity. We examined the effect of repeated low and medium doses versus single high dose of methamphetamine on degeneration of dopaminergic terminals and cell bodies. Mice were given methamphetamine in one of the following paradigms: three injections of 5 or 10 mg/kg at 3 h intervals or a single 30 mg/kg injection. The integrity of dopaminergic fibers and cell bodies were assessed at different time points after methamphetamine by TH-immunohistochemistry and silver-staining. The 3 × 10 protocol yielded the highest loss of striatal dopaminergic terminals, followed by the 3 × 5 and 1 × 30. Some degenerating axons could be followed from the striatum to the SNpc. All protocols induced similar significant degeneration of dopaminergic neurons in the SNpc, evidenced by amino-cupric-silver-stained dopaminergic neurons. These neurons died by necrosis and apoptosis. Methamphetamine also killed striatal neurons. By using D1-Tmt/D2-GFP BAC transgenic mice, we observed that degenerating striatal neurons were equally distributed between direct and indirect MSN. Despite the reduced number of dopaminergic neurons in the SNpc at 30 days post-treatment, there was a partial time-dependent recovery of dopamine terminals beginning 3d post-treatment. Locomotor activity and motor coordination were robustly decreased 1-3d post-treatment, but recovered at later times along with dopaminergic terminals. These data provide direct evidence that methamphetamine causes long-lasting loss/degeneration of dopaminergic cell bodies in the SNpc, along with destruction of dopaminergic terminals in the striatum.Neuropsychopharmacology accepted article preview online, 30 October 2013; doi:10.1038/npp.2013.307.