Increased Vesicular Monoamine Transporter 2 (VMAT2; Slc18a2) Protects against Methamphetamine Toxicity

ACS Chemical Neuroscience
Kelly M LohrGary W Miller

Abstract

The psychostimulant methamphetamine (METH) is highly addictive and neurotoxic to dopamine terminals. METH toxicity has been suggested to be due to the release and accumulation of dopamine in the cytosol of these terminals. The vesicular monoamine transporter 2 (VMAT2; SLC18A2) is a critical mediator of dopamine handling. Mice overexpressing VMAT2 (VMAT2-HI) have an increased vesicular capacity to store dopamine, thus augmenting striatal dopamine levels and dopamine release in the striatum. Based on the altered compartmentalization of intracellular dopamine in the VMAT2-HI mice, we assessed whether enhanced vesicular function was capable of reducing METH-induced damage to the striatal dopamine system. While wildtype mice show significant losses in striatal levels of the dopamine transporter (65% loss) and tyrosine hydroxylase (46% loss) following a 4 × 10 mg/kg METH dosing regimen, VMAT2-HI mice were protected from this damage. VMAT2-HI mice were also spared from the inflammatory response that follows METH treatment, showing an increase in astroglial markers that was approximately one-third of that of wildtype animals (117% vs 36% increase in GFAP, wildtype vs VMAT2-HI). Further analysis also showed that elevated VMAT2 level doe...Continue Reading

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Citations

Jan 28, 2016·Analytical Chemistry·Joseph R MazzulliHarry Ischiropoulos
Jun 12, 2016·Toxicological Sciences : an Official Journal of the Society of Toxicology·Kelly M LohrGary W Miller
Aug 16, 2016·The European Journal of Neuroscience·Kelly M LohrGary W Miller
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Feb 5, 2021·Toxicological Sciences : an Official Journal of the Society of Toxicology·Joshua M BradnerGary W Miller
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Dec 31, 2020·Chemical Research in Toxicology·Carlie A BlackGary W Miller
Oct 3, 2018·ACS Chemical Neuroscience·Julian MaierHarald H Sitte

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