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