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.[27]
Induction
To date, no agent has been shown to directly interact with SLC18A2 in a way that promotes its activity. A VMAT2 positive allosteric modulator remains an elusive target in addiction and Parkinson's disease research.[28][29] However, it has been observed that certain tricylcic and tetracylcic antidepressants (as well as a high-mesembrineSceletium tortuosum extract) can upregulate the activity of VMAT2 in vitro, though whether this is due to a direct interaction is unknown.[30][31]
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.[32][33] Hamer himself notes that SLC18A2 plays at most a minor role in influencing spirituality.[34] Furthermore, Hamer's claim that the SLC18A2 gene contributes to spirituality is controversial.[34] 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.[34][35]
^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 Archiv. 447 (5): 636–640. 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". Progress in Neurobiology. 75 (6): 406–433. 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)
^Pifl C, Reither H, Hornykiewicz O (May 2015). "The profile of mephedrone on human monoamine transporters differs from 3,4-methylenedioxymethamphetamine primarily by lower potency at the vesicular monoamine transporter". Eur J Pharmacol. 755: 119–126. doi:10.1016/j.ejphar.2015.03.004. PMID25771452.
^Cozzi NV, Sievert MK, Shulgin AT, Jacob P, Ruoho AE (September 1999). "Inhibition of plasma membrane monoamine transporters by beta-ketoamphetamines". Eur J Pharmacol. 381 (1): 63–69. doi:10.1016/s0014-2999(99)00538-5. PMID10528135.
^Simmler LD (2018). "Monoamine Transporter and Receptor Interaction Profiles of Synthetic Cathinones". Synthetic Cathinones. Vol. 12. Cham: Springer International Publishing. p. 97–115. doi:10.1007/978-3-319-78707-7_6. ISBN978-3-319-78706-0. While the determination of drug effects at the isolated target (i.e., DAT, NET, and SERT) can characterize the direct drug action at the target protein, other physiological components can also contribute significantly to the overall effect of the drug. It has been proposed that transporter-mediated, drug-induced efflux of neurotransmitter occurs through effects on the vesicular monoamine transporter 2 (VMAT2), depleting neurotransmitter from the vesicles into the cytosol (Nickell et al. 2014). Accordingly, full assessment of release would require testing the effects of a drug on the membrane transporters (SERT, DAT, and NET) and the effects of a drug at VMAT2. Alternatively, a more physiological system, such as synaptosomes or brain slices, could be used. However, reverse transport can also occur in cell lines that only express the plasma membrane transporters but not VMAT2 (Eshleman et al. 2013; Scholze et al. 2000) and in synaptosomes when VMAT2 is inhibited (Rothman et al. 2001).
^Halberstadt AL, Brandt SD, Walther D, Baumann MH (March 2019). "2-Aminoindan and its ring-substituted derivatives interact with plasma membrane monoamine transporters and α2-adrenergic receptors". Psychopharmacology (Berl). 236 (3): 989–999. doi:10.1007/s00213-019-05207-1. PMC6848746. PMID30904940. In contrast to assay systems involving non-neuronal cells transfected with transporter proteins, synaptosomes possess all of the cellular machinery necessary for neurotransmitter synthesis, release, metabolism, and reuptake. Synaptosomes, however, do not model all of the effects of amphetamine-type agents because the use of reserpine removes any contribution of the vesicular monoamine transporter VMAT2 (SLC18A2) to the release process. In addition to acting as a substrate for plasma membrane monoamine transporters, amphetamine also binds to VMAT, resulting in the redistribution of monoamines from vesicular stores to the cytoplasm (Sulzer et al. 1995; Partilla et al. 2006; Freyberg et al. 2016). Although transporter substrates can induce monoamine release in the absence of VMAT binding (Fon et al. 1997), it is important to recognize that 2-aminoindans may have effects in intact nerve terminals that are not fully replicated in synaptosomes. Follow-up studies will be conducted to evaluate whether 2-aminoindans are capable of interacting with VMAT.
^Rotolo RA, Presby RE, Tracy O, Asar S, Yang JH, Correa M, et al. (February 2021). "The novel atypical dopamine transport inhibitor CT-005404 has pro-motivational effects in neurochemical and inflammatory models of effort-based dysfunctions related to psychopathology". Neuropharmacology. 183: 108325. doi:10.1016/j.neuropharm.2020.108325. PMID32956676.
^ abProvencher BA, Eshleman AJ, Johnson RA, Shi X, Kryatova O, Nelson J, et al. (October 2018). "Synthesis and Discovery of Arylpiperidinylquinazolines: New Inhibitors of the Vesicular Monoamine Transporter". J Med Chem. 61 (20): 9121–31. doi:10.1021/acs.jmedchem.8b00542. PMID30240563.
^Chandler CM, Nickell JR, George Wilson A, Culver JP, Crooks PA, Bardo MT, et al. (October 2024). "Vesicular monoamine transporter-2 inhibitor JPC-141 prevents methamphetamine-induced dopamine toxicity and blocks methamphetamine self-administration in rats". Biochem Pharmacol. 228: 116189. doi:10.1016/j.bcp.2024.116189. PMC 11546627. PMID38580165.
^Little KY, Krolewski DM, Zhang L, Cassin BJ (January 2003). "Loss of striatal vesicular monoamine transporter protein (VMAT2) in human cocaine users". The American Journal of Psychiatry. 160 (1): 47–55. doi:10.1176/appi.ajp.160.1.47. PMID12505801.
^Coetzee DD, López V, Smith C (January 2016). "High-mesembrine Sceletium extract (Trimesemine™) is a monoamine releasing agent, rather than only a selective serotonin reuptake inhibitor". Journal of Ethnopharmacology. 177: 111–6. doi:10.1016/j.jep.2015.11.034. PMID26615766.
^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.
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Watabe M, Nakaki T (October 2008). "Mitochondrial complex I inhibitor rotenone inhibits and redistributes vesicular monoamine transporter 2 via nitration in human dopaminergic SH-SY5Y cells". Molecular Pharmacology. 74 (4): 933–940. doi:10.1124/mol.108.048546. PMID18599602. S2CID1844073.
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