Role of hyperthermia in the protective action of clomethiazole against MDMA (‘ecstasy’)‐induced neurodegeneration, comparison with the novel NMDA channel blocker AR‐R15896AR
María Isabel Colado, R Granados, Esther O’shea, B. Moreno Esteban, A R Green
British Journal of Pharmacology June 1, 1998 DOI: 10.1038/sj.bjp.0701859 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | MDMA clomethiazole |
| Dose | 15 mg/kg MDMA i.p., 20 mg/kg AR-R15896AR i.p., 50 mg/kg clomethiazole i.p. |
| Duration | 5 hours post-MDMA for temperature manipulation, 7 days for neurodegeneration assessment |
| Topics | MDMA |
| Keywords | Pharmacology Nmda receptor Neuroprotection Neurotoxicity Hyperthermia Striatum Hippocampus Anesthesia Agonist Dizocilpine |
| Citations | 80 |
| Key findings | Clomethiazole protects against MDMA-induced serotonin nerve terminal damage partly by reducing hyperthermia and partly by a temperature-independent mechanism, while an NMDA receptor blocker offers no protection unless it induces hypothermia. |
Abstract
The immediate effect of administration of 3,4‐methylenedioxymethamphetamine (MDMA or ‘ecstasy’) on rectal temperature and the effect of putative neuroprotective agents on this change has been examined in rats. The influence of the temperature changes on the long term MDMA‐induced neurodegeneration of cerebral 5‐hydroxytryptamine (5‐HT) nerve terminals was also examined. The novel low affinity N‐methyl‐ D ‐aspartate (NMDA) receptor channel blocker AR‐R15896AR (20 mg kg −1 , i.p.) given 5 min before and 55 min after MDMA (15 mg kg −1 , i.p.) did not prevent the MDMA‐induced hyperthermia and did not alter either the MDMA‐induced neurodegenerative loss of 5‐HT and 5‐hydroxyindoleacetic acid (5‐HIAA) in cortex, striatum and hippocampus or loss of [ 3 H]‐paroxetine binding in cortex 7 days later. The neuroprotective agent clomethiazole (50 mg kg −1 , i.p.) given 5 min before and 55 min after MDMA (15 mg kg −1 ) abolished the MDMA‐induced hyperthermic response and markedly attenuated the loss of 5‐HT, 5‐HIAA and [ 3 H]‐paroxetine binding in the brain regions examined 7 days later. When rats treated with MDMA plus clomethiazole were kept at high ambient temperature for 5 h post‐MDMA, thereby keeping their body temperature elevated to near that seen in rats given MDMA alone, the MDMA‐induced loss of 5‐HT, 5‐HIAA and [ 3 H]‐paroxetine was still attenuated. However, the protection (39%) afforded by the clomethiazole administration was less than seen in rats kept at normal ambient temperature (75%). These data support the proposals of others that NMDA receptor antagonists are neuroprotective against MDMA‐induced degeneration only if they induce hypothermia and further suggest that increased glutamate activity may not be involved in the neurotoxic action of MDMA. These data further demonstrate that a proportion of the neuroprotective action of clomethiazole is due to an effect on body temperature but that, in addition, the compound protects against MDMA‐induced damage by an unrelated mechanism.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 32
- Neurotoxicity of Methamphetamine and 3,4-methylenedioxymethamphetamine Life Science July 24, 2013
- Neurotoxicity of methylenedioxyamphetamines (MDMA; ecstasy) in humans: how strong is the evidence for persistent brain damage? Addiction February 27, 2006
- A study of the mechanisms involved in the neurotoxic action of 3,4‐methylenedioxymethamphetamine (MDMA, ‘ecstasy’) on dopamine neurones in mouse brain British Journal of Pharmacology December 1, 2001
- Neurotoxicity of drugs of abuse - the case of methylenedioxy amphetamines (MDMA, ecstasy ), and amphetamines Dialogues in Clinical Neuroscience September 30, 2009
- Ascorbic acid prevents 3,4-methylenedioxymethamphetamine (MDMA)-induced hydroxyl radical formation and the behavioral and neurochemical consequences of the depletion of brain 5-HT Synapse 2001
and 27 more in the library
Cites 14
- 3,4‐Methylenedioxymethamphetamine (MDMA, “Ecstasy”): pharmacology and toxicology in animals and humans Addiction May 1, 1994
- A study of the neurotoxic effect of MDMA (‘ecstasy’) on 5‐HT neurones in the brains of mothers and neonates following administration of the drug during pregnancy British Journal of Pharmacology June 1, 1997
- In vivo evidence for free radical involvement in the degeneration of rat brain 5‐HT following administration of MDMA (‘ecstasy’) and p‐chloroamphetamine but not the degeneration following fenfluramine British Journal of Pharmacology July 1, 1997
- The hyperthermic and neurotoxic effects of ‘Ecstasy’ (MDMA) and 3,4 methylenedioxyamphetamine (MDA) in the Dark Agouti (DA) rat, a model of the CYP2D6 poor metabolizer phenotype British Journal of Pharmacology August 1, 1995
- Age-dependent sensitivity of rats to the long-term effects of the serotonergic neurotoxicant (+/-)-3,4-methylenedioxymethamphetamine (MDMA) correlates with the magnitude of the MDMA-induced thermal response. Journal of Pharmacology and Experimental Therapeutics October 1, 1995
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