Concurrent Inhibition of Vesicular Monoamine Transporter 2 Does Not Protect Against 3,4-Methylenedioxymethamphetamine (Ecstasy) Induced Neurotoxicity.
Aram B Cholanians, Andy V Phan, Serrine S. Lau, Terrence J. Monks
Toxicological sciences : an official journal of the Society of Toxicology July 1, 2019 DOI: 10.1093/toxsci/kfz085 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Sprague Dawley rats |
| Interventions | MDMA Ro 4-1284 |
| Dose | MDMA 20, 25, or 27.5 mg/kg sc; Ro 4-1284 10 mg/kg ip |
| Topics | MDMA |
| Keywords | Ro 4-1284 Vmat2 Hyperthermia Neurotoxicity |
| Key findings | Co- or posttreatment with the VMAT2 inhibitor Ro 4-1284 shortened MDMA-induced hyperthermia (about 3 hours versus 8 hours) but did not significantly reduce indolamine depletion in any MDMA-treated group. The authors suggest that VMAT2 inhibition's neuroprotective effects are likely due to Ro 4-1284's indirect monoamine-depleting action rather than direct VMAT2 inhibition. |
Abstract
3, 4-Methylenedioxymethamphetamine (MDMA) is a hallucinogenic amphetamine derivative. The acute effects of MDMA are hyperthermia, hyperactivity, and behavioral changes, followed by long-term serotonergic neurotoxicity in rats and primates. However, the underlying mechanisms of MDMA neurotoxicity remain elusive. We reported that pretreatment of rats with Ro 4-1284, a reversible inhibitor of the vesicular monoamine transporter 2 (VMAT2), reduced MDMA-induced hyperactivity in rats, abolished the hyperthermic response, and the long-term neurotoxicity. Current studies focused on the effects of co- and/or postinhibition of VMAT2 on the acute and chronic effects of MDMA and on the dose-response relationship between MDMA-induced elevations in body temperature and subsequent reductions in indolamine concentrations. Sprague Dawley rats were treated with MDMA (20, 25, or 27.5 mg/kg sc), and either co- and/or posttreatment with the VMAT2 inhibitor (10 mg/kg ip). Rats simultaneously treated with Ro 4-1284 and MDMA exhibited a more rapid increase in body temperature compared to just MDMA. However, the duration of the elevated body temperature was significantly shortened (approximately 3 h vs approximately 8 h, respectively). A similar body temperature response was observed in rats posttreated (7 h after MDMA) with Ro 4-1284. Despite decreases in the area under the curve (Δtemp X time) of body temperature caused by Ro 4-1284, there were no significant differences in the degree of indolamine depletion between any of the MDMA-treated groups. The results suggest that the neuroprotective effects of VMAT2 inhibition is likely due to the indirect monoamine depleting effects of the Ro 4-1284 pretreatment, rather than by the direct inhibition of VMAT2 function.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 2
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