Vesicular monoamine transporter 2 and the acute and long-term response to 3,4-(±)- methylenedioxymethamphetamine

Lucina E. Lizarraga, Aram B. Cholanians, Andy V. Phan, Joseph M. Herndon, Serrine Lau, Terrence Monks

Research output: Contribution to journalArticle

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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. MDMAinduced 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.

Original languageEnglish (US)
Article numberkfu222
Pages (from-to)209-219
Number of pages11
JournalToxicological Sciences
Volume143
Issue number1
DOIs
StatePublished - Jan 1 2015

Fingerprint

Vesicular Monoamine Transport Proteins
N-Methyl-3,4-methylenedioxyamphetamine
2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-2H-benzo(a)quinolizin-2-ol
Serotonin
Rats
Corpus Striatum
Induced Hyperthermia
Methamphetamine
Product Packaging
Amphetamine
Body Temperature

Keywords

  • Hyperactivity
  • Hyperthermia
  • MDMA
  • Neurotoxicity
  • Ro4-1284
  • VMAT2

ASJC Scopus subject areas

  • Toxicology

Cite this

Vesicular monoamine transporter 2 and the acute and long-term response to 3,4-(±)- methylenedioxymethamphetamine. / Lizarraga, Lucina E.; Cholanians, Aram B.; Phan, Andy V.; Herndon, Joseph M.; Lau, Serrine; Monks, Terrence.

In: Toxicological Sciences, Vol. 143, No. 1, kfu222, 01.01.2015, p. 209-219.

Research output: Contribution to journalArticle

Lizarraga, Lucina E. ; Cholanians, Aram B. ; Phan, Andy V. ; Herndon, Joseph M. ; Lau, Serrine ; Monks, Terrence. / Vesicular monoamine transporter 2 and the acute and long-term response to 3,4-(±)- methylenedioxymethamphetamine. In: Toxicological Sciences. 2015 ; Vol. 143, No. 1. pp. 209-219.
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