The psychostimulant methamphetamine (MA) is toxic to nigro‐striatal dopaminergic terminals in both experimental animals and humans. In mice, three consecutive injections of MA (5 mg/kg, i.p. with 2 h of interval) induced a massive degeneration of the nigro‐striatal pathway, as reflected by a 50% reduction in the striatal levels of dopamine (DA) and 3,4‐dihydroxyphenylacetic acid (DOPAC), by a substantial reduction in striatal tyrosine hydroxylase and high‐affinity DA transporter immunostaining, and by the development of reactive gliosis. MA‐induced nigro‐striatal degeneration was largely attenuated in mice lacking α1b‐adrenergic receptors (ARs). MA‐stimulated striatal DA release (measured by microdialysis in freely moving animals) and locomotor activity were also reduced in α1b‐AR knockout mice. Pharmacological blockade of α‐adrenergic receptors with prazosin also protected wild‐type mice against MA toxicity. These results suggests that α1b‐ARs may play a role in the toxicity of MA on nigro‐striatal DA neurons.