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MDMA (Ecstasy) and Human Dopamine, Norepinephrine, and Serotonin Transporters: Implications for MDMA-Induced Neurotoxicity and Treatment

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MDMA (Ecstasy) and Human Dopamine, Norepinephrine, and Serotonin Transporters: Implications for MDMA-Induced Neurotoxicity and Treatment Psychopharmacology (2007) 189: 489–503 DOI 10.1007/s00213-005-0174-5 ORIGINAL INVESTIGATION Christopher D. Verrico . Gregory M. Miller . Bertha K. Madras MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment Received: 31 May 2005 / Accepted: 17 August 2005 / Published online: 12 October 2005 # Springer-Verlag 2005 Abstract Rationale: 3,4-Methylenedioxymethamphet- tion of [3H](±, RS)- (+, S)- and (−, R)-MDMA with the amine (MDMA, designated as “Ecstasy” if illicitly mar- human SERT, dopamine (DA) transporter (DAT), and keted in tablet form) induces significant decrements in norepinephrine (NE) transporter (NET) in stably transfected neuronal serotonin (5-HT) markers in humans, nonhuman human embryo kidney (HEK)-293 cells. Results: The primates, and rats as a function of dosing and dosing human DAT, NET, and SERT actively transported [3H]RS regimen. In rats, MDMA-mediated effects are attributed, (±)-MDMA saturably, stereoselectively, and in a tempera- in part, to selective high-affinity transport of MDMA ture-, concentration-, and transporter-dependent manner. into 5-HT neurons by the 5-HT transporter (SERT), fol- MDMA exhibited the highest affinity for the NET≫SERT≥- lowed by extensive 5-HT release. Objectives: To clarify DAT, the same rank order for MDMA inhibition of [3H]DA, whether SERT-selective effects of MDMA at human [3H]NE, and [3H]5-HT transport and stimulated release of monoamine transporters can account for the reported the [3H]monoamines, which differed from reports derived MDMA-induced selective toxicity of serotonin neurons from rodent monoamine transporters. The extent of in primate brain. Methods: We investigated the interac- MDMA-induced release of 5-HT was higher compared with release of DA or NE. Conclusions: The affinity of This research was presented by C. Verrico et al. in abstract forms MDMA for the human SERT in transfected cells does not at the annual meeting of the Society for Neuroscience 2003 and clarify the apparent selective toxicity of MDMA for 2004. serotonin neurons, although conceivably, its higher efficacy Klaus A. Miczek as Principal Editor—the special issue for stimulating 5-HT release may be a distinguishing factor. “A Contemporary View of MDMA.” The findings highlight the need to investigate MDMA effects in DAT-, SERT-, and NET-expressing neurons in the . C. D. Verrico G. M. Miller B. K. Madras primate brain and the therapeutic potential of NET or DAT Department of Psychiatry, Division of Neurochemistry, New England Primate Research Center, inhibitors, in addition to SERT-selective inhibitors, for Harvard Medical School, alleviating the pharmacological effects of MDMA. 1 Pine Hill Drive, Southborough, MA 01772-9102, USA Keywords MDMA . Ecstasy . Dopamine . Serotonin . C. D. Verrico . G. M. Miller . B. K. Madras Norepinephrine Transporters Trace amine receptors Nuclear Medicine Division, Massachusetts General Hospital, Monoamines . Reuptake inhibitors Boston, MA 02114, USA B. K. Madras (*) Division of Neurochemistry, New England Primate Research Center, Harvard Medical School, Introduction 1 Pine Hill Drive, Southborough, MA 01772-9102, USA In the mammalian brain, 3,4-methylenedioxymethamphe- e-mail: [email protected] Tel.: +1-508-6248073 tamine (MDMA) induces selective decrements in markers Fax: +1-508-6248166 of monoamine neurons as a function of dose, dosing regimen, and species (Ricaurte et al. 1988a). These changes Present address: can persist for years after the last exposure (Bowyer et al. C. D. Verrico Center for the Neural Basis of Cognition, 113 Mellon Institute, 2003; Taffe et al. 2002, 2003; Reneman et al. 2002; 4400 Fifth Avenue, Hatzidimitriou et al. 1999; Scheffel et al. 1998; Nash and Pittsburgh, PA 15213, USA Yamamoto 1992; Slikker et al. 1989). The most consistent 490 and prominent findings in the primate brain are reductions (Km values), and incomplete evidence that MDMA is a in brain serotonin (5-HT), its major metabolite 5-hydroxy- substrate for human monoamine transporters may compro- indoleacetic acid (5-HIAA), the 5-HT transporter (SERT), mise this extrapolation. To fill this void, we interrogated the and tryptophan hydroxylase (Ricaurte et al. 1988a,b, 1992). influence of MDMA at human monoamine transporters. In humans, the 5-HT system is also most notably affected, Foremost, we determined whether the relative potencies of with reduced cerebrospinal fluid levels of 5-HT and 5- MDMA for inhibiting rodent monoamine transporters HIAA and reduced SERT binding potential in the brain extended to human monoamine transporters. Second, we (Steele et al. 1994; Buchert et al. 2004;McCannetal.2005). determined directly whether [3H]MDMA is sequestered by These findings are postulated to reflect MDMA-induced cells expressing human monoamine transporters and com- neurotoxicity and to account for the neuropsychological pared substrate affinities with MDMA potencies for inhib- effects of prolonged exposure to MDMA (Parrott 2001). iting human DAT, NET, and SERT. This represents the first Nevertheless, extrapolation from biochemical markers to direct evidence of DAT-, NET-, and SERT-mediated [3H] neuronal damage or death in humans remains equivocal MDMA transport into cells and supports the view of (Turner and Parrott 2000;Kish2002; Check 2004). MDMA as a substrate based on MDMA-induced ion con- Although MDMA-induced release of serotonin via the ductances (Sonders et al. 1997). To further explore the SERT is frequently cited as the significant mechanism in substrate properties of MDMA, we compared MDMA MDMA-induced neurotoxicity, this postulate remains affinities for inhibiting radiolabeled inhibitor binding to the controversial. Other underlying causes have been proposed, DAT, NET, and SERT with affinities for blocking mono- including carrier-dependent transport of MDMA, metabolic amine transport, as substrates display relatively weak toxic products, oxidative stress, hyperthermia, apoptosis, affinities at radioligand binding sites, whereas transport and increased extracellular concentrations of dopamine inhibitor potencies at radiolabeled sites usually correspond (DA) and 5-HT (Simantov and Tauber 1997;Shankaran to their affinities for blocking the transport of monoamines et al. 1999; Sanchez et al. 2001; Green et al. 2003). (Madras et al. 1989a,b;Gouletetal.2001;Eshlemanetal. The selective effects of MDMA on 5-HT neurons are 1995, 1999). Our third objective was to monitor the species-dependent. Serotonin neurons of the primate brain capacity of MDMA to release sequestered monoamines are more susceptible to MDMA-induced changes when from transporter-expressing cultured cells, as MDMA compared to rats (Ricaurte and McCann 1992; Slikker et al. promotes monoamine release in vivo (except NE) and in 1988, 1989), whereas in mice, MDMA selectively modifies vitro (Yamamoto and Spanos 1988; Johnson et al. 1986; DA neurons while sparing 5-HT neurons (Logan et al. Fitzgerald and Reid 1990; Gough et al. 1991; Gudelsky and 1988;O’Callaghan and Miller 1994; Xie et al. 2004). Dose Nash 1996; Rothman et al. 2001; Zaczek et al. 1990; and dosing regimen are another contributing factor to O’Shea et al. 2001; Mechan et al. 2002; Nash and Brodkin MDMA-induced neurotoxicity, as high doses of MDMA 1991; Koch and Galloway 1997). promotes dopaminergic and noradrenergic neurotoxicity in Conceivably, data derived from cell lines expressing the rats (Commins et al. 1987; Mayerhofer et al. 2001). cloned human transporters may not fully reflect transporter However, the susceptibility of catecholamine neurons to pharmacology in human neurons. This is unlikely, as the MDMA-induced neurotoxicity is unresolved in primates pharmacological specificities of drugs at biogenic amine (Turner and Parrott 2000). transporters expressed in various regions of a macaque The divergent neurotoxic properties of substituted am- monkey’s primate brain corresponded closely (r2=0.93 for phetamines are postulated, among others, to be due to NET, 0.98 for DAT, and 0.99 for SERT) to affinities differences in potencies at monoamine transporters (Rudnick derived from cell lines expressing cloned macaque monkey and Wall 1992). The serotonin neuron-selective toxicity of transporters (Miller et al. 2001). MDMA has been attributed to its higher affinity, uptake, or For the first time, we demonstrate the transport of [3H] releasing capacity at the SERT, compared with the dopamine MDMA by human monoamine transporters in a stereospe- transporter (DAT) or norepinephrine (NE) transporter (NET, cific-, concentration-, time-, and temperature-dependent Rudnick and Wall 1992). This view is supported by data manner. Contrary to conclusions drawn from rat transport- derived from the rodent brain, in which MDMA displays a ers, MDMA did not display selective effects at the human tenfold higher affinity for blocking SERT-mediated 5-HT SERT compared with the DATor the NET. Indeed, MDMA transport compared with its affinity for the DAT (Steele et al. affinity for the human NET was higher than for DAT or 1987; Battaglia et al. 1988). In contrast, amphetamine se- SERT, warranting further investigation of the functional lectively affects DA neurons, and methamphetamine appar- and therapeutic significance of NET–MDMA interactions. ently affects both neuronal subtypes, coinciding with their relative potencies at the three monoamine transporters (see McCann and Ricaurte 2004 for a review). Methods The conventional hypothesis that MDMA is toxic to serotonin neurons
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