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Vesicular monoamine transporter 2 and the acute and long-term response to 3,4-(±)-methylenedioxymethamphetamine.
Toxicol Sci 2015; 143(1):209-19TS

Abstract

3,4-(±)-Methylenedioxymethamphetamine (MDMA, Ecstasy) is a ring-substituted amphetamine derivative with potent psychostimulant properties. The neuropharmacological effects of MDMA are biphasic in nature, initially causing synaptic monoamine release, primarily of serotonin (5-HT). Conversely, the long-term effects of MDMA manifest as prolonged depletions in 5-HT, and reductions in 5-HT reuptake transporter (SERT), indicative of serotonergic neurotoxicity. MDMA-induced 5-HT efflux relies upon disruption of vesicular monoamine storage, which increases cytosolic 5-HT concentrations available for release via a carrier-mediated mechanism. The vesicular monoamine transporter 2 (VMAT2) is responsible for packaging monoamine neurotransmitters into cytosolic vesicles. Thus, VMAT2 is a molecular target for a number of psychostimulant drugs, including methamphetamine and MDMA. We investigated the effects of depressed VMAT2 activity on the adverse responses to MDMA, via reversible inhibition of the VMAT2 protein with Ro4-1284. A single dose of MDMA (20 mg/kg, subcutaneous) induced significant hyperthermia in rats. Ro4-1284 (10 mg/kg, intraperitoneal) pretreatment prevented the thermogenic effects of MDMA, instead causing a transient decrease in body temperature. MDMA-treated rats exhibited marked increases in horizontal velocity and rearing behavior. In the presence of Ro4-1284, MDMA-mediated horizontal hyperlocomotion was delayed and attenuated, whereas rearing activity was abolished. Finally, Ro4-1284 prevented deficits in 5-HT content in rat cortex and striatum, and reduced depletions in striatal SERT staining, 7 days after MDMA administration. In summary, acute inhibition of VMAT2 by Ro4-1284 protected against MDMA-mediated hyperthermia, hyperactivity, and serotonergic neurotoxicity. The data suggest the involvement of VMAT2 in the thermoregulatory, behavioral, and neurotoxic effects of MDMA.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721.Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721.Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721.Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721.Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721.Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721 monks@pharmacy.arizona.edu.

Pub Type(s)

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

Language

eng

PubMed ID

25370842

Citation

Lizarraga, Lucina E., et al. "Vesicular Monoamine Transporter 2 and the Acute and Long-term Response to 3,4-(±)-methylenedioxymethamphetamine." Toxicological Sciences : an Official Journal of the Society of Toxicology, vol. 143, no. 1, 2015, pp. 209-19.
Lizarraga LE, Cholanians AB, Phan AV, et al. Vesicular monoamine transporter 2 and the acute and long-term response to 3,4-(±)-methylenedioxymethamphetamine. Toxicol Sci. 2015;143(1):209-19.
Lizarraga, L. E., Cholanians, A. B., Phan, A. V., Herndon, J. M., Lau, S. S., & Monks, T. J. (2015). Vesicular monoamine transporter 2 and the acute and long-term response to 3,4-(±)-methylenedioxymethamphetamine. Toxicological Sciences : an Official Journal of the Society of Toxicology, 143(1), pp. 209-19. doi:10.1093/toxsci/kfu222.
Lizarraga LE, et al. Vesicular Monoamine Transporter 2 and the Acute and Long-term Response to 3,4-(±)-methylenedioxymethamphetamine. Toxicol Sci. 2015;143(1):209-19. PubMed PMID: 25370842.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Vesicular monoamine transporter 2 and the acute and long-term response to 3,4-(±)-methylenedioxymethamphetamine. AU - Lizarraga,Lucina E, AU - Cholanians,Aram B, AU - Phan,Andy V, AU - Herndon,Joseph M, AU - Lau,Serrine S, AU - Monks,Terrence J, Y1 - 2014/11/04/ PY - 2014/11/6/entrez PY - 2014/11/6/pubmed PY - 2016/1/6/medline KW - MDMA KW - Ro4-1284 KW - VMAT2 KW - hyperactivity KW - hyperthermia KW - neurotoxicity SP - 209 EP - 19 JF - Toxicological sciences : an official journal of the Society of Toxicology JO - Toxicol. Sci. VL - 143 IS - 1 N2 - 3,4-(±)-Methylenedioxymethamphetamine (MDMA, Ecstasy) is a ring-substituted amphetamine derivative with potent psychostimulant properties. The neuropharmacological effects of MDMA are biphasic in nature, initially causing synaptic monoamine release, primarily of serotonin (5-HT). Conversely, the long-term effects of MDMA manifest as prolonged depletions in 5-HT, and reductions in 5-HT reuptake transporter (SERT), indicative of serotonergic neurotoxicity. MDMA-induced 5-HT efflux relies upon disruption of vesicular monoamine storage, which increases cytosolic 5-HT concentrations available for release via a carrier-mediated mechanism. The vesicular monoamine transporter 2 (VMAT2) is responsible for packaging monoamine neurotransmitters into cytosolic vesicles. Thus, VMAT2 is a molecular target for a number of psychostimulant drugs, including methamphetamine and MDMA. We investigated the effects of depressed VMAT2 activity on the adverse responses to MDMA, via reversible inhibition of the VMAT2 protein with Ro4-1284. A single dose of MDMA (20 mg/kg, subcutaneous) induced significant hyperthermia in rats. Ro4-1284 (10 mg/kg, intraperitoneal) pretreatment prevented the thermogenic effects of MDMA, instead causing a transient decrease in body temperature. MDMA-treated rats exhibited marked increases in horizontal velocity and rearing behavior. In the presence of Ro4-1284, MDMA-mediated horizontal hyperlocomotion was delayed and attenuated, whereas rearing activity was abolished. Finally, Ro4-1284 prevented deficits in 5-HT content in rat cortex and striatum, and reduced depletions in striatal SERT staining, 7 days after MDMA administration. In summary, acute inhibition of VMAT2 by Ro4-1284 protected against MDMA-mediated hyperthermia, hyperactivity, and serotonergic neurotoxicity. The data suggest the involvement of VMAT2 in the thermoregulatory, behavioral, and neurotoxic effects of MDMA. SN - 1096-0929 UR - https://www.unboundmedicine.com/medline/citation/25370842/Vesicular_monoamine_transporter_2_and_the_acute_and_long_term_response_to_34__±__methylenedioxymethamphetamine_ L2 - https://academic.oup.com/toxsci/article-lookup/doi/10.1093/toxsci/kfu222 DB - PRIME DP - Unbound Medicine ER -