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MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment.
Psychopharmacology (Berl). 2007 Jan; 189(4):489-503.P

Abstract

RATIONALE

3,4-Methylenedioxymethamphetamine (MDMA, designated as "Ecstasy" if illicitly marketed in tablet form) induces significant decrements in neuronal serotonin (5-HT) markers in humans, nonhuman primates, and rats as a function of dosing and dosing regimen. In rats, MDMA-mediated effects are attributed, in part, to selective high-affinity transport of MDMA into 5-HT neurons by the 5-HT transporter (SERT), followed by extensive 5-HT release.

OBJECTIVES

To clarify whether SERT-selective effects of MDMA at human monoamine transporters can account for the reported MDMA-induced selective toxicity of serotonin neurons in primate brain.

METHODS

We investigated the interaction of [(3)H](+/-, RS)- (+, S)- and (-, R)-MDMA with the human SERT, dopamine (DA) transporter (DAT), and norepinephrine (NE) transporter (NET) in stably transfected human embryo kidney (HEK)-293 cells.

RESULTS

The human DAT, NET, and SERT actively transported [(3)H]RS(+/-)-MDMA saturably, stereoselectively, and in a temperature-, concentration-, and transporter-dependent manner. MDMA exhibited the highest affinity for the NET>>SERT>or=DAT, the same rank order for MDMA inhibition of [(3)H]DA, [(3)H]NE, and [(3)H]5-HT transport and stimulated release of the [(3)H]monoamines, which differed from reports derived from rodent monoamine transporters. The extent of MDMA-induced release of 5-HT was higher compared with release of DA or NE.

CONCLUSIONS

The affinity of MDMA for the human SERT in transfected cells does not clarify the apparent selective toxicity of MDMA for serotonin neurons, although conceivably, its higher efficacy for stimulating 5-HT release may be a distinguishing factor. The findings highlight the need to investigate MDMA effects in DAT-, SERT-, and NET-expressing neurons in the primate brain and the therapeutic potential of NET or DAT inhibitors, in addition to SERT-selective inhibitors, for alleviating the pharmacological effects of MDMA.

Authors+Show Affiliations

Department of Psychiatry, Division of Neurochemistry, New England Primate Research Center, Harvard Medical School, 1 Pine Hill Drive, Southborough, MA 01772-9102, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16220332

Citation

Verrico, Christopher D., et al. "MDMA (Ecstasy) and Human Dopamine, Norepinephrine, and Serotonin Transporters: Implications for MDMA-induced Neurotoxicity and Treatment." Psychopharmacology, vol. 189, no. 4, 2007, pp. 489-503.
Verrico CD, Miller GM, Madras BK. MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment. Psychopharmacology (Berl). 2007;189(4):489-503.
Verrico, C. D., Miller, G. M., & Madras, B. K. (2007). MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment. Psychopharmacology, 189(4), 489-503.
Verrico CD, Miller GM, Madras BK. MDMA (Ecstasy) and Human Dopamine, Norepinephrine, and Serotonin Transporters: Implications for MDMA-induced Neurotoxicity and Treatment. Psychopharmacology (Berl). 2007;189(4):489-503. PubMed PMID: 16220332.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment. AU - Verrico,Christopher D, AU - Miller,Gregory M, AU - Madras,Bertha K, Y1 - 2005/10/12/ PY - 2005/05/31/received PY - 2005/08/17/accepted PY - 2005/10/13/pubmed PY - 2007/3/3/medline PY - 2005/10/13/entrez SP - 489 EP - 503 JF - Psychopharmacology JO - Psychopharmacology (Berl.) VL - 189 IS - 4 N2 - RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA, designated as "Ecstasy" if illicitly marketed in tablet form) induces significant decrements in neuronal serotonin (5-HT) markers in humans, nonhuman primates, and rats as a function of dosing and dosing regimen. In rats, MDMA-mediated effects are attributed, in part, to selective high-affinity transport of MDMA into 5-HT neurons by the 5-HT transporter (SERT), followed by extensive 5-HT release. OBJECTIVES: To clarify whether SERT-selective effects of MDMA at human monoamine transporters can account for the reported MDMA-induced selective toxicity of serotonin neurons in primate brain. METHODS: We investigated the interaction of [(3)H](+/-, RS)- (+, S)- and (-, R)-MDMA with the human SERT, dopamine (DA) transporter (DAT), and norepinephrine (NE) transporter (NET) in stably transfected human embryo kidney (HEK)-293 cells. RESULTS: The human DAT, NET, and SERT actively transported [(3)H]RS(+/-)-MDMA saturably, stereoselectively, and in a temperature-, concentration-, and transporter-dependent manner. MDMA exhibited the highest affinity for the NET>>SERT>or=DAT, the same rank order for MDMA inhibition of [(3)H]DA, [(3)H]NE, and [(3)H]5-HT transport and stimulated release of the [(3)H]monoamines, which differed from reports derived from rodent monoamine transporters. The extent of MDMA-induced release of 5-HT was higher compared with release of DA or NE. CONCLUSIONS: The affinity of MDMA for the human SERT in transfected cells does not clarify the apparent selective toxicity of MDMA for serotonin neurons, although conceivably, its higher efficacy for stimulating 5-HT release may be a distinguishing factor. The findings highlight the need to investigate MDMA effects in DAT-, SERT-, and NET-expressing neurons in the primate brain and the therapeutic potential of NET or DAT inhibitors, in addition to SERT-selective inhibitors, for alleviating the pharmacological effects of MDMA. SN - 0033-3158 UR - https://www.unboundmedicine.com/medline/citation/16220332/MDMA__Ecstasy__and_human_dopamine_norepinephrine_and_serotonin_transporters:_implications_for_MDMA_induced_neurotoxicity_and_treatment_ L2 - https://dx.doi.org/10.1007/s00213-005-0174-5 DB - PRIME DP - Unbound Medicine ER -