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 S. Lau, Terrence J. Monks
Toxicological sciences : an official journal of the Society of Toxicology January 2015 DOI: 10.1093/toxsci/kfu222 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experiment (rat) Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | MDMA Ro4-1284 |
| Dose | MDMA 20 mg/kg subcutaneous; Ro4-1284 10 mg/kg intraperitoneal |
| Duration | 7 days after MDMA administration |
| Topics | MDMA |
| Keywords | Ro4-1284 Vmat2 Hyperactivity Hyperthermia Neurotoxicity |
| Key findings | Pretreatment with the VMAT2 inhibitor Ro4-1284 (10 mg/kg) prevented MDMA-induced hyperthermia (causing a transient temperature decrease instead), delayed and attenuated MDMA-induced horizontal hyperlocomotion, abolished rearing, and prevented serotonin depletions in cortex and striatum and reduced striatal SERT loss 7 days after a single 20 mg/kg MDMA dose. The authors suggest VMAT2 is involved in MDMA's thermoregulatory, behavioral, and neurotoxic effects. |
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.
Comparable studies
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