SLC18A2 is believed to possess at least two distinct binding sites, which are characterized by tetrabenazine (TBZ) and reserpine binding to the transporter.[8]Amphetamine (TBZ site) and methamphetamine (reserpine site) bind at distinct sites on SLC18A2 to inhibit its function.[8] SLC18A2 inhibitors like tetrabenazine and reserpine reduce the concentration of monoamine neurotransmitters in the synaptic cleft by inhibiting uptake through SLC18A2; the inhibition of SLC18A2 uptake by these drugs prevents the storage of neurotransmitters in synaptic vesicles and reduces the quantity of neurotransmitters that are released through exocytosis. Although many substituted amphetamines induce the release of neurotransmitters from vesicles through SLC18A2 while inhibiting uptake through SLC18A2, they may facilitate the release of monoamine neurotransmitters into the synaptic cleft by simultaneously reversing the direction of transport through the primary plasma membrane transport proteins for monoamines (i.e., the dopamine transporter, norepinephrine transporter, and serotonin transporter) in monoamine neurons. Other SLC18A2 inhibitors such as GZ-793A inhibit the reinforcing effects of methamphetamine, but without producing stimulant or reinforcing effects themselves.[9]
Researchers have found that inhibiting the dopamine transporter (but not SLC18A2) will block the effects of amphetamine and cocaine; while, in another experiment, observing that disabling SLC18A2 (but not the dopamine transporter) prevents any notable action in test animals after amphetamine administration yet not cocaine administration. This suggests that amphetamine may be an atypical substrate with little to no ability to prevent dopamine reuptake via binding to the dopamine transporter but, instead, uses it to enter a neuron where it then interacts with SLC18A2 to induce efflux of dopamine from their vesicles into the cytoplasm whereupon dopamine transporters with amphetamine substrates attached move this recently liberated dopamine into the synaptic cleft.[10]
Cocaine users display a marked reduction in SLC18A2 immunoreactivity. Those with cocaine-induced mood disorders displayed a significant loss of SLC18A2 immunoreactivity; this might reflect damage to dopamine axon terminals in the striatum. These neuronal changes could play a role in causing disordered mood and motivational processes in more severely addicted users.[11]
Geneticist Dean Hamer has suggested that a particular allele of the SLC18A2 gene correlates with spirituality using data from a smoking survey, which included questions intended to measure "self-transcendence". Hamer performed the spirituality study on the side, independently of the National Cancer Institute smoking study. His findings were published in the mass-market book The God Gene: How Faith Is Hard-Wired into Our Genes.[12][13] Hamer himself notes that SLC18A2 plays at most a minor role in influencing spirituality.[14] Furthermore, Hamer's claim that the SLC18A2 gene contributes to spirituality is controversial.[14] Hamer's study has not been published in a peer-reviewed journal and a reanalysis of the correlation demonstrates that it is not statistically significant.[14][15]
^Eiden LE, Schäfer MK, Weihe E, Schütz B (February 2004). "The vesicular amine transporter family (SLC18): amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine". Pflügers Arch. 447 (5): 636–40. doi:10.1007/s00424-003-1100-5. PMID12827358. S2CID20764857.
^ abSulzer D, Sonders MS, Poulsen NW, Galli A (April 2005). "Mechanisms of neurotransmitter release by amphetamines: a review". Prog. Neurobiol. 75 (6): 406–33. doi:10.1016/j.pneurobio.2005.04.003. PMID15955613. S2CID2359509. They also demonstrated competition for binding between METH and reserpine, suggesting they might bind to the same site on VMAT. George Uhl's laboratory similarly reported that AMPH displaced the VMAT2 blocker tetrabenazine (Gonzalez et al., 1994). Tetrabenazine and reserpine are thought to bind to different sites on VMAT (Schuldiner et al., 1993a)
^Kluger J, Chu J, Liston B, Sieger M, Williams D (25 October 2004). "Is God in our genes?". TIME. Time Inc. Archived from the original on 30 September 2007. Retrieved 8 April 2007.
Harris PE, Ferrara C, Barba P, Polito T, Freeby M, Maffei A (2008). "VMAT2 gene expression and function as it applies to imaging beta-cell mass". J. Mol. Med. 86 (1): 5–16. doi:10.1007/s00109-007-0242-x. PMID17665159. S2CID20374043.
Watabe M, Nakaki T (2008). "Mitochondrial complex I inhibitor rotenone inhibits and redistributes vesicular monoamine transporter 2 via nitration in human dopaminergic SH-SY5Y cells". Mol. Pharmacol. 74 (4): 933–40. doi:10.1124/mol.108.048546. PMID18599602. S2CID1844073.
Yosifova A, Mushiroda T, Stoianov D, Vazharova R, Dimova I, Karachanak S, Zaharieva I, Milanova V, Madjirova N, Gerdjikov I, Tolev T, Velkova S, Kirov G, Owen MJ, O'Donovan MC, Toncheva D, Nakamura Y (2009). "Case-control association study of 65 candidate genes revealed a possible association of a SNP of HTR5A to be a factor susceptible to bipolar disease in Bulgarian population". J Affect Disord. 117 (1–2): 87–97. doi:10.1016/j.jad.2008.12.021. PMID19328558.
Crowley JJ, Lipsky RH, Lucki I, Berrettini WH (2008). "Variation in the genes encoding vesicular monoamine transporter 2 and beta-1 adrenergic receptor and antidepressant treatment outcome". Psychiatr. Genet. 18 (5): 248–51. doi:10.1097/YPG.0b013e3283052ff7. PMID18797399. S2CID206148319.
Guo JT, Chen AQ, Kong Q, Zhu H, Ma CM, Qin C (2008). "Inhibition of vesicular monoamine transporter-2 activity in alpha-synuclein stably transfected SH-SY5Y cells". Cell. Mol. Neurobiol. 28 (1): 35–47. doi:10.1007/s10571-007-9227-0. PMID17985233. S2CID20230170.
