Alpha-1B adrenergic receptor knockout mice are protected against metamphetamine toxicity

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 alpha1b-adrenergic receptors (ARs). MA-stimulated striatal DA release (measured by microdialysis in freely moving animals) and locomotor activity were also reduced in alpha1b-AR knockout mice. Pharmacological blockade of alpha-adrenergic receptors with prazosin also protected wild-type mice against MA toxicity. These results suggests that alpha1b-ARs may play a role in the toxicity of MA on nigro-striatal DA neurons.