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Increased methamphetamine neurotoxicity in heterozygous vesicular monoamine transporter 2 knock-out mice
F Fumagalli1, R R Gainetdinov, Y M Wang
1Howard Hughes Medical Institute Laboratories, Departments of Cell Biology and Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Abstract:
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.
Insights
Impaired vesicular transport potentiates methamphetamine (METH) neurotoxicity. This suggests intraneuronal dopamine redistribution, not just overflow, drives METH
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- Methamphetamine (METH) abuse is a global health concern.
- Dopaminergic system dysfunction and dopamine oxidation are implicated in METH neurotoxicity.
- The specific source of dopamine mediating METH neurotoxicity remains unclear.
Purpose of the Study:
- To investigate the role of vesicular monoamine transporter 2 (VMAT2) function in METH neurotoxicity.
- To determine if impaired vesicular transport alters METH's effects on the dopaminergic system.
Main Methods:
- Utilized VMAT2 heterozygous mice (VMAT2 +/-) and wild-type littermates.
- Assessed METH-induced neurotoxicity by measuring dopamine and metabolite levels, and dopamine transporter expression in the striatum.
- Monitored extracellular dopamine levels and markers of free radical formation.
Main Results:
- VMAT2 +/- mice exhibited increased METH-induced neurotoxicity compared to wild-type mice.
- This included greater dopamine depletion and reduced dopamine transporter expression in VMAT2 +/- mice.
- Interestingly, VMAT2 +/- mice showed less extracellular dopamine increase and reduced free radical formation.
Conclusions:
- Disruption of vesicular monoamine transport enhances METH-induced neurotoxicity in vivo.
- Findings indirectly suggest that intraneuronal dopamine redistribution plays a larger role than extraneuronal overflow in METH neurotoxicity.