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Schmitt & Reith DAT Regulation Figure 2. Metabolic reaction pathway of MDA-like compounds leading to the formation of neurotoxic prooxidant thioether species and the relative toxicity of metabolites. The parent compounds MDA and MDMA are not directly cytotoxic. 131,132 However, demethylenation of the 3,4-methylenedioxy moiety by the hepatic CYP2D6 enzyme 135 results in the formation of 3,4-dihydroxyamphetamines, which are readily oxidized to quinones. 134 These quinones can form conjugates with GSH, greatly potentiating neurotoxicity. 138 Further metabolism in the brain via the mercapturic acid pathway results in toxic NAC-conjugated species. Although the quinones, GSH-conjugates, and NAC-conjugates all promote the formation of reactive oxygen species, NAC-substituted compounds appear to possess the greatest relativistic potential for toxicity owing to their protracted rate of elimination from the brain. 137 (In color in Annals online.) in vivo. 136,137 Quinones are strong electrophiles: they can serve to propagate ROS via a one-electron redox reaction to a stable semiquinone radical or form conjugates with reducing agents via two-electron nucleophilic attack. 138 In particular, the dopaminoquinone-like metabolite of MDA/MDMA can undergo conjugation with the cysteinyl thiol moiety of the endogenous reductant glutathione (GSH) to form the thioether 5-(glutathionyl)-�-methyldopamine (5-(GSH)- �MeDA) or its N-methyl analogue. 136 In the central nervous system, the 5-(glutathionyl)-thioethers are ultimately metabolized via the mercapturic acid pathway to form 5-(N-acetyl-cysteinyl)- �-methyldopamine (5-(NAC)-�MeDA) and its N-methyl analogue (5-(NAC)-�,N-diMeDA). The structural formulae of these metabolites and their relative potencies as neurotoxins are displayed in Figure 2. The thioether metabolites are potent serotonergic neurotoxins that can induce a dose-dependent increase in ROS formation and cause caspase-3–mediated apoptosis in cultured cortical neurons. 137 Moreover, direct intrastriatal administration of pure 5-(NAC)-�,N-diMeDA in rats fully recapitulates the serotonergic toxicity observed with systemic high-dose MDMA. 136 These thioethers are detectable in the rat brain after systemic administration of a high-dose neurotoxic regimen of MDMA—repeated dosing leads to significant accumulation due to a nonlinear increase in elimination half-life. 139 Interestingly, cotreatment with the antioxidant GSH precursor N-acetylcysteine (NAC) successfully protects cultured cortical neurons from thioether-induced apoptosis and attenuates the formation of ROS, even though NAC could Ann. N.Y. Acad. Sci. 1187 (2010) 316–340 c○ 2010 New York Academy of Sciences. 331
DAT Regulation Schmitt & Reith obviously contribute to the formation of the 5-(NAC)-thioether metabolites. 137 Pretreatment with the antioxidant compound acetyl-L-carnitine was also shown to prevent oxidative damage to neuronal mitochondria in vivo after high-dose MDMA administration in rats. 140 These data strongly indicate that the toxicity of MDMA and its analogues is due chiefly to oxidative stress induced by the potent and selective serotonergic neurotoxins formed during metabolism of the parent compound. Moreover, these findings suggest that avoidance of repeated dosing and concomitant use of central nervous system–penetrating antioxidant compounds are prudent harm reduction strategies for preventing or limiting the damage inherent to recreational MDMA use. If the neurotoxic effects of the MDA-type ring substituted amphetamines is due primarily to the formation of prooxidant quinone metabolites, what can be said of amphetamine derivatives that are unlikely to form such unstable metabolites, such as d-methamphetamine? Despite being similar to amphetamine itself in structure, pharmacokinetics, and metabolic fate, methamphetamine exhibits increased toxicity and significantly greater abuse potential than the parent compound. 20,141 Toxic insult to both serotonergic and dopaminergic neuronal systems after high doses of d-methamphetamine has been routinely demonstrated in experimental animals (see Cadet et al. 142 for a review). In humans, chronic high-dose methamphetamine addicts show moderate deficits in cognitive function, and in vivo neuroimaging techniques reveal decreased surface DAT concentration 143 and increased microglial activation compared with control subjects. 144 Eventual recovery from these effects appears possible, but normalization of dopaminergic function is an extremely slow process, taking months to years. 145 Similarly to neurotoxicity associated with MDA-like substituted amphetamines, the toxic response to methamphetamine—particularly in dopaminergic neurons—also involves oxidative stress by quinonemediated formation of ROS and subsequent activation of proapoptotic signaling cascades. 142 Findings that antioxidant compounds can reduce neurotoxic insult by methamphetamine support of this theory: for example, high doses of the aforementioned antioxidant NAC ameliorate the longterm loss of striatal DAT in moneys after repeated injections of methamphetamine. 146 However, un- like with MDA/MDMA, here the likely culprit is not a metabolic product of the parent stimulant but rather dopamine itself. Free-floating dopamine (that is, existing outside synaptic vesicles) can be spontaneously oxidized to dopaminoquinone and successively converted to 5-cysteinyl-catechol thioethers in a manner identical to the reaction of the MDA metabolite 3,4dihydroxyamphetamine shown in Figure 2. 147 If sufficiently large concentrations of soluble dopamine are present, mechanisms to rapidly clear or safely inactivate dopamine—namely, the DAT and the catabolic enzyme COMT—will presumably be saturated. Excess dopamine will thus be nonspecifically oxidized, resulting in dose-dependent formation of dopaminoquinone. How might this oxidative mechanism explain the increased toxicity of methamphetamine compared with amphetamine itself? A series of experiments by Goodwin et al. systematically highlighted, for the first time, some vital differences between the two compounds in their respective effects on the DAT and dopaminergic function. 20 Notably, the authors demonstrated that d-methamphetamine is fivefold more effective at stimulating the DAT to release dopamine in hDAT-expressing HEK cells than d-amphetamine at identical concentrations. Also, in vivo chronoamperometry in the rat nucleus accumbens after administration of an equivalent dose of either methamphetamine or amphetamine (5 mg/kg) revealed that methamphetamine significantly prolonged dopamine clearance time compared with amphetamine, resulting in greater sustained external dopamine levels. However, no differences between the two were detected at a 1-mg/kg dose (Ref. 20, Fig. 5). Thesedatasuggestthatathigh(yetequivalent) doses, methamphetamine has a far greater propensity than amphetamine to produce accumulation of excess external dopamine. The higher resultant concentrations of external dopamine conceivably contribute to the greater addictive potential of methamphetamine than with amphetamine and may also render methamphetamine more likely to cause oxidative neurodegeneration. Although the specific DAT-mediated pharmacology of methamphetamine contributes to its particularly high toxicity and abuse potential, another basic contributing factor is the dose and administration pattern typical of human methamphetamine addicts. Recreational 332 Ann. N.Y. Acad. Sci. 1187 (2010) 316–340 c○ 2010 New York Academy of Sciences.
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