Low ambient temperature reveals distinct mechanisms for MDMA-induced serotonergic toxicity and astroglial Hsp27 heat shock response in rat brain

Abstract

3,4-Methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is a widely used recreational drug known to cause selective long-term serotonergic damage. In our recent paper we described region-specific, dose-dependent increase in the protein expression of astroglial Hsp27 and neuronal Hsp72 molecular chaperones after MDMA administration of rats. Here, we examined the possible interaction of elevated Hsp27 protein level to hyperthermic responses after MDMA administration and its separation from drug-induced serotonergic neurotoxicity. For this, 7–8week old male Dark Agouti rats were treated with 15mg/kg i.p. MDMA. Treatment at an ambient temperature of 22±1°C caused a significant elevation of the rectal temperature, an increase of Hsp27 immunoreactive protoplasmic astrocytes in the hippocampus, the parietal and cingulate cortices, and a significant decrease in the density of tryptophan hydroxylase immunoreactive fibers in the same brain regions, 8h as well as 24h after drug administrations. In addition, serotonergic axons exhibited numerous swollen varicosities and fragmented morphology. MDMA treatment at low ambient temperature (10±2°C) almost completely abolished the elevation of body temperature and the increased astroglial Hsp27 expression but failed to alter – or just slightly attenuated – the depletion in the density of tryptophan hydroxylase immunoreactive fibers. These results suggest that the increased astroglial Hsp27 protein expression is rather related to the hyperthermic response after the drug administration and it could be separated from the serotonergic neurotoxicity caused by MDMA. In addition, the induction of Hsp27 per se is uneffective to protect serotonergic fibers after MDMA administration. Our results also suggest that Tph immunohistochemistry is an early and sensitive method to demonstrate MDMA-caused vulnerability.