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The Journal of Neuroscience, April 1, 1999, 19(7):2424-2431

Increased Methamphetamine Neurotoxicity in Heterozygous Vesicular Monoamine Transporter 2 Knock-Out Mice

Fabio Fumagalli, Raul R. Gainetdinov, Yan-Min Wang, Kenneth J. Valenzano, Gary W. Miller, and Marc G. Caron

Howard Hughes Medical Institute Laboratories, Departments of Cell Biology and Medicine, Duke University Medical Center, Durham, North Carolina 27710

Methamphetamine (METH) is a powerful psychostimulant that is increasingly abused worldwide. Although it is commonly accepted that the dopaminergic system 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 whether impaired vesicular function alters the effects of METH. METH-induced dopaminergic neurotoxicity was increased in striatum of VMAT2 +/ mice compared with wild-type mice as revealed by a more consistent DA and metabolite depletion and a greater decrease in dopamine transporter expression. Interestingly, increased METH neurotoxicity in VMAT2 +/ mice was accompanied by less pronounced increase in extracellular DA and indices of free radical formation compared with wild-type mice. These results indicate that disruption of vesicular monoamine transport potentiates METH-induced neurotoxicity in vivo and point, albeit indirectly, to a greater contribution of intraneuronal DA redistribution rather than extraneuronal overflow on mediating this effect.

Key words: vesicular monoamine transporter; methamphetamine; dopamine; microdialysis; GFAP; free radicals

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Copyright © 1999 Society for Neuroscience  0270-6474/99/1972424-08$05.00/0

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