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Studies on the neuroprotective effect of pentobarbitone on MDMA-induced neurodegeneration
M I Colado1, B Esteban, E O'Shea
1Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Madrid, Spain. colado@eucmax.sim.ucm.es
Abstract:
Administration of a dose of 15 mg/kg of the recreationally used drug 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") to Dark Agouti rats resulted in an acute hyperthermic response which was followed 7 days later by a marked (approximately 45%) loss of 5-HT and its metabolite 5-HIAA in cortex, hippocampus and striatum and a similar loss of [3H]-paroxetine binding in cortex. These losses reflect the MDMA-induced neurotoxic degeneration of 5-HT nerve endings. Administration of pentobarbitone (40 mg/kg) concurrently with MDMA produced a significant attenuation of the neurotoxic damage, but also acute hypothermia. When the temperature of the MDMA plus pentobarbitone-treated group was kept elevated to that of the MDMA-treated group by the use of a homeothermic blanket, the neuroprotective effect of pentobarbitone was lost. These data demonstrate that pentobarbitone appears to possess no intrinsic neuroprotective activity and the previously reported activity is due to a hypothermic action of the drug.
Insights
Pentobarbitone reduces ecstasy (MDMA) neurotoxicity in rats, but only when it causes hypothermia. This effect is lost if body temperature is maintained, indicating pentobarbitone lacks intrinsic neuroprotective properties.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- 3,4-methylenedioxymethamphetamine (MDMA, or "ecstasy") is a recreational drug known to cause hyperthermia and neurotoxic effects.
- Previous studies suggested pentobarbitone may protect against MDMA-induced neurotoxicity.
Purpose of the Study:
- To investigate the neuroprotective mechanism of pentobarbitone against MDMA neurotoxicity.
- To determine if pentobarbitone's neuroprotective effect is intrinsic or related to its hypothermic action.
Main Methods:
- Administration of MDMA (15 mg/kg) to Dark Agouti rats.
- Concurrent administration of pentobarbitone (40 mg/kg) with MDMA.
- Maintaining normothermia in a subset of MDMA and pentobarbitone-treated rats using a homeothermic blanket.
- Assessing 5-HT, 5-HIAA levels, and [3H]-paroxetine binding in brain regions.
Main Results:
- MDMA caused hyperthermia and a significant loss of 5-HT, 5-HIAA, and [3H]-paroxetine binding in rat brain regions.
- Concurrent pentobarbitone administration attenuated MDMA neurotoxicity but induced hypothermia.
- The neuroprotective effect of pentobarbitone was abolished when body temperature was artificially maintained at normal levels.
Conclusions:
- Pentobarbitone's apparent neuroprotective effect against MDMA is solely due to its ability to induce hypothermia.
- Pentobarbitone does not possess intrinsic neuroprotective activity against MDMA-induced neurotoxicity.
- Body temperature plays a critical role in the neurotoxic effects of MDMA.