localized on small clear-core or large-dense-core vesicles. the activated heterotrimeric g-protein gαq downregulates vmat2-mediated serotonin transport in blood platelets, but not in the brain, where gαq completely inhibits vmat2 activity. although the exact signalling pathway for g-protein mediated regulation of vmats is not known, it has recently been described that implicated g-proteins act directly on the vmats. clinical significance vmat2 has been shown to contribute to many clinical neurological disorders including drug addiction, mood disorders, and stress, as well as parkinson's disease and alzheimer's disease. parkinson's disease studies indicate vmat2 mrna is present in all cell groups damaged by parkinson's disease (pd); these findings have identified vmat2 as a target for preventing parkinson's. vmat2 presence does not independently protect neurons from pd, but a decrease in vmat2 expression has been shown to correlate with susceptibility to the disease, which may be due to a ratio between the dopamine transporter and vmat2. based on the understanding the increased cytosolic dopamine levels lead to dopaminergic cell death in pd, it has been proposed that regulatory polymorphisms in vmat2 affect vmat2 quantitative expression, and may serve as a genetic risk factor for pd. specifically, the slc18a2 promoter region for the vmat2 gene has been identified as an area where several polymorphisms form discrete haplotypes. mood disorders studies using a genetic rodent model to understand clinical depression in humans suggest that vmat2 genetic or functional alterations may be involved in depression. reduced vmat2 levels were identified in specific subregions of the striatum involved in clinical depression, including the nucleus accumbens shell but not the core, the ventral tegmental area, and the substantia nigra's pars compacta. the reduced vmat2 protein levels were not accompanied by similar levels of vmat2 mrna alterations. based on these findings, it has been proposed that vmat2 activity is not altered at the level of genetic expression, but may be altered at the functional level in ways that may correlate with clinical depression. drug addiction many psychostimulant drugs are known to interact with vmat, including amphetamine analogs such as methamphetamine, cocaine, and ecstasy (mdma). pharmacology vmat inhibitors tend to fall into two classes; those that interact with the res binding site and those that interact with the tbz binding site. res, methoxytetrabenazine, and amiodarone bind to the res binding site. tbz, dtbzoh, ketanserin, and lobeline bind to the tbz binding site. substituted amphetamines, including but not limited to methamphetamine and cocaine, are known to interact with vmat2. studies indicate that both amphetamines and cocaine act to increase non-exocytotic release of dopamine in specific 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 in dtbzoh binding in humans. research suggests a decline in vmat2 protein through prolonged cocaine use could play an important role in the development of cocaine-induced mood disorders. mdma mdma is known to affect serotonergic neurons, but has been shown to inhibit synaptosomal and vesicular uptake of serotonin and dopamine to roughly the same extent in vitro. in vivo studies indicate short-term mdma exposure causes short-term reduction in vmat2 activity, which is reversed after 24 hours. current research clinical research genetic research models have shown that polymorphisms in slc18a1 and slc18a2, the genes that encode for vmat1 and 2 proteins, respectively, may confer risk for some neuropsychiatric disorders; however, no specific diseases have been identified yet as directly resulting from a genetic mutation in an slc18 gene, which codes for vmat proteins. much of the current research related to vmat explores the genetic underpinnings of neuropsychiatric disorders as they may be affected by slc18a family mutations. the dopaminergic neuron is known to play a central role in drug addiction and abuse and the potential role of the dopamine transporter has been well-explored as a target for amphetamine and cocaine. current research looks toward vmat2 as a target for such psychostimulants. a combination of imaging, neurochemical, biochemical, cell biological, genetic, and immunohistochemical evidence has been compiled to provide the most current comprehensive understanding of the role the vmat2 plays in amphetamine and cocaine abuse and addiction through aminergic neurotransmission. as vmats are membrane proteins, structural information is limited and researchers have yet to completely understand the structure of both isoforms. further studies are needed in order to determine the structure and therefore complete function of these proteins. there is preliminary evidence that the gene for vmat1 may be linked to susceptibility to schizophrenia, bipolar disorder, and various anxiety disorders. further studies are needed in order to confirm these findings and to gain a better understanding of the role of vmats in the central nervous system. multiple single-nucleotide polymorphisms (snps) have been identified in the coding region of vmats. the effects of some of these snps have been alteration of vmat function, structure and regulation. further investigation of these snps is required in order to distinguish whether they may be attributable to certain diseases with suspected snp-mutation origins. α-synuclein, a cytosolic protein found mainly in pre-synaptic nerve terminals, has been found to have regulatory interactions with the trafficking of vmats; mutations involving α-synuclein have been linked to familial pd. further research is needed to clarify the extent to which these proteins modulate the trafficking of vmats, and whether they may be exploited in order to gather more information about the exact mechanism of how disorders such as pd occurs, and how they may potentially be treated. studies have shown that at the synaptic membrane, enzymes responsible for the synthesis of dopamine, tyrosine hydroxylase and amino acid aromatic decarboxylase are physically and functionally coupled with vmat2. it was initially thought that the synthesis of these substances and the subsequent packaging of them into vesicles were two entirely separate processes. animal research current research related to vmat uses vmat2 knockout mice to explore the behavioral genetics of this transporter in an animal model. vmat2 knockouts are known to be lethal as homozygotes, but heterozygote knockouts are not lethal and are used in many studies as a durable animal model. from knockout and knockdown mice, researchers have discovered that it is good to have over-expression or under-expression of the vmat genes in some circumstances. mice are also used in drug studies, particularity studies involving the effect cocaine and methamphetamine have on vmats. studies involving animals have prompted scientists to work on developing drugs that inhibit or enhance the function of vmats. drugs that inhibit vmats may have use in addiction but further studies are needed. enhancing the function of vmats may also have therapeutic value.