Increased methamphetamine neurotoxicity in heterozygous vesicular monoamine transporter 2 knock-out mice

Methamphetamine (METH) is a powerful psychostimulant that is increasingly a bused worldwide. Although it is commonly accepted that the dopaminergic sys tem and oxidation of dopamine (DA) play pivotal roles in the neurotoxicity produced by this phenylethylamine, the primary source of DA responsible for this effect has remained elusive. In this study, we used mice heterozygous for vesicular monoamine transporter 2 (VMAT2 +/- mice) to determine whethe r impaired vesicular function alters the effects of METH. METH-induced dopa minergic neurotoxicity was increased in striatum of VMAT2 +/- mice compared with wild-type mice as revealed by a more consistent DA and metabolite dep letion and a greater decrease in dopamine transporter expression. Interesti ngly, increased METH neurotoxicity in VMAT2 +/- mice was accompanied by les s pronounced increase in extracellular DA and indices of free radical forma tion compared with wild-type mice. These results indicate that disruption o f vesicular monoamine transport potentiates METH-induced neurotoxicity in v ivo and point, albeit indirectly, to a greater contribution of intraneurona l DA redistribution rather than extraneuronal overflow on mediating this ef fect.