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Acute administration of 3,4-methylenedioxymethamphetamine induces profound hyperthermia, blood-brain barrier disruption, brain edema formation, and cell injury: An Experimental Study in Rats and Mice Using Biochemical and Morphologic Approaches
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
2008 (English)In: DRUG ADDICTION: RESEARCH FRONTIERS AND TREATMENT ADVANCES / [ed] Kuhar MJ, Kuhar MJ, 2008, Vol. 1139, 242-258 p.Conference paper (Refereed)
Abstract [en]

The psychostimulant 3,4-,ethylenedioxymethamphetamine (MDMA, "ecstasy") is known to induce hyperthermia and alterations in neurochemical metabolism in the CNS. However, the detailed cellular or molecular mechanisms behind MDMA-induced neurotoxicity are still not well known. Since MDMA induces profound hyperthermia that could lead to intense cellular stress and cause disruption of the blood-brain barrier (BBB), this investigation examined the effects of acute MDMA on BBB dysfunction, brain edema, and cell injury in rats and mice. When MDMA (40 mg/kg, i.p.) was administered to rats or mice, these animals exhibited profound behavioral disturbances (hyperactivity and hyperlocomotion) and hyperthermia (>40 to 41 degrees C) at 4 h. At this time, the leakage of Evans blue dye was evident, particularly in the cerebellum, hippocampus, cortex, thalamus, and hypothalamus. This effect was most pronounced in mice compared to rats. Marked increase in brain water along with Na(+), K(+), and Cl(-) content was also seen in the aforementioned brain regions. Presence of distorted neuronal and glial cells in brain regions associated with leakage of Evans blue is quite common in MDMA-treated animals. Increased albumin immunoreactivity, indicating breakdown of the BBB, and upregulation of glial fibrillary acidic protein (GFAP), suggesting activation of astrocytes, were seen in most brain regions showing edematous changes. Upregulation of heat-shock protein (HSP72) immunoreactivity in the nuclei and cell cytoplasm of the neurons located in the edematous brain regions are quite common. Taken together, these observations are the first to show that MDMA has the capacity to disrupt BBB permeability to proteins and to induce the formation of edema, probably by inducing hyperthermia and cellular stress, as evident with HSP overexpression leading to cell injury.

Place, publisher, year, edition, pages
2008. Vol. 1139, 242-258 p.
, Annals of the New York Academy of Sciences, ISSN 0077-8923 ; 1139
Keyword [en]
3; 4-methylenedioxymethamphetamine (MDMA), ecstasy, blood-brain barrier (BBB), brain edema, Evans blue, heat-shock protein (HSP), glial fibrillary acidic protein (GFAP), serum albumin, neuronal injury, brain damage, hyperthermia
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-88088DOI: 10.1196/annals.1432.052ISI: 000261167100029PubMedID: 18991870ISBN: 978-1-57331-718-4OAI: oai:DiVA.org:uu-88088DiVA: diva2:134340
1st International Drug-Abuse-Research-Society Merida, MEXICO, AUG 14-17, 2007
Available from: 2009-01-20 Created: 2009-01-20 Last updated: 2011-04-21Bibliographically approved

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