Editing Vesicular monoamine transporter (section)

===Methamphetamine===
VMAT is a main target of methamphetamine. Studies indicate that substituted amphetamines including methamphetamine interact with VMAT2 at the TBZ/DTBZOH binding site.<ref name="Wimalasena, K. 2011"/><ref name="Fleckenstein AE 2007"/> By acting as a [[competitive antagonist|negative allosteric modulator]], methamphetamine blocks the presynaptic cell's ability to use VMAT for vesicular packaging.

Methamphetamine alters the subcellular location of VMAT2, which affects the distribution of dopamine in the cell. Treatment with methamphetamine relocates VMAT2 from a vesicle-enriched [[Cell fractionation|fraction]] to a location that is not continuous with synaptosomal preparations.<ref name="Wimalasena, K. 2010"/>

Repeated amphetamine exposure may increase VMAT2 mRNA in certain brain regions with little or no decline upon withdrawal from the drug.<ref name="Wimalasena, K. 2010"/>

A study performed by Sonsalla ''et al.'' demonstrated that methamphetamine treatment decreases DHTBZ binding and vesicular dopamine uptake.<ref name="Wimalasena, K. 2011"/><ref name="Fleckenstein AE 2007"/> Another study demonstrated that multiple high doses of methamphetamine removed DTBZ binding sites from the vesicles.<ref name="Chaudhry FA 2007"/>

In addition to an interaction with the TBZ/DTBZOH binding site, some researchers propose that substituted amphetamines like methamphetamine decrease dopamine uptake because of the weak base properties of substituted amphetamines.<ref name="Fleckenstein AE 2007"/> This “Weak Base Hypothesis” proposes that amphetamine analogs enter the cell through transport and lipophilic diffusion, then diffuses through the vesicular membrane where they accumulate in synaptic vesicles and offset the proton electrochemical gradient in the vesicle that drives monoamine transport through VMAT.<ref name="Fleckenstein AE 2007"/> Amphetamine administration would prevent vesicular dopamine uptake through VMAT, and explain the finding that amphetamine administration correlates with decreased dopamine release from vesicles and a neurotoxic increase in intracellular dopamine.<ref name="Wimalasena, K. 2011"/><ref name="Fleckenstein AE 2007"/>