regions of the brain by interacting directly with VMAT2 function. Methamphetamine VMAT is a main target of methamphetamine. Studies indicate that substituted amphetamines including methamphetamine interact with VMAT2 at the TBZ/DTBZOH binding site. By acting as a competitive antagonist, 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 fraction to a location that is not continuous with synaptosomal preparations. Repeated amphetamine exposure may increase VMAT2 mRNA in certain brain regions with little or no decline upon withdrawal from the drug. A study performed by Sonsalla et al. demonstrated that methamphetamine treatment decreases DHTBZ binding and vesicular dopamine uptake. Another study demonstrated that multiple high doses of methamphetamine removed DTBZ binding sites from the vesicles. 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. 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. 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. Cocaine Unlike methamphetamine, cocaine interacts with VMAT2 by mobilizing VMAT2-expressing vesicles, causing a shift in VMAT2 proteins from a plasmalemmal (synaptosomal) membrane fraction to a vesicle-enriched fraction that is not associated with the synaptosomal membrane and not retained in synaptosomal preparations. Methylphenidate is believed to interact with VMAT2 in a similar fashion. In addition to mobilizing VMAT2-expressing vesicles, cocaine has been shown to increase the Vmax of VMAT2 for dopamine and increase the number of DTBZ binding sites. It has also mobilized a synapsin-dependent reserve pool of dopamine-containing synaptic vesicles, which interacts with the vesicular trafficking cycle to increase dopamine release. Short-term exposure to cocaine increases VMAT2 density in the prefrontal cortex and striatum of mammalian brains. This is theorized to be a defensive mechanism against the depletive effects cocaine has on cytosolic dopamine through increasing monoamine storage capacity. Chronic cocaine use has been implicated with a reduction in VMAT2 immunoreactivity as well as a decrease