1. ¹Laboratoire de Neurosciences Comportementales et Cognitives, UMR 7521, CNRS/Université Louis Pasteur, GDR 2905 CNRS, IFR 37 Neurosciences, Strasbourg, France
2. ²Institut für Experimentelle und Klinische Pharmakologie und Toxikologie der Universität Freiburg, Neuropharmakologisches Labor, Freiburg, Germany
3. ³Biobehavioral Health, The Pennsylvania State University, University Park, PA, USA

Correspondence: Dr J-C Cassel, Laboratoire de Neurosciences Comportementales et Cognitives, LN2C, UMR 7521, CNRS/Université Louis Pasteur, GDR 2905 CNRS, IFR 37 Neurosciences, 12 rue Goethe, Strasbourg F-67000, France. Tel: +33 390 241 952; Fax: +33 390 241 958; E-mail: jean-christophe.cassel@psycho-ulp.u-strasbg.fr

Received 29 November 2004; Revised 26 January 2005; Accepted 31 January 2005; Published online 23 March 2005.

Abstract

This study investigated long-term behavioral, neurochemical, and neuropharmacological effects of ethanol–()-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) combinations. Over 4 consecutive days, male Long–Evans rats received 1.5 g/kg ethanol and/or 10 mg/kg MDMA, or saline. Rectal temperatures were taken in some rats. Starting 4 days after the last injection, we tested working memory, sensory–motor coordination, and anxiety. Subsequently, we measured cortical, striatal, septal, and hippocampal monoamines (last MDMA injection–euthanasia delay: 20 days), or electrically evoked release of serotonin (5-HT) in cortical and hippocampal slices, and its modulation in the presence of CP 93,129 (3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrollo[3,2-b]pyrid-5-one) or methiotepin (last MDMA injection–euthanasia delays: 3–6 weeks). Ethanol attenuated the MDMA-induced hyperthermia, but only on the first day. In the long-term, MDMA reduced 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) content in most brain regions. The behavioral and neurochemical effects of the ethanol–MDMA combination were comparable to those of MDMA alone; sensory–motor coordination was altered after ethanol and/or MDMA. In hippocampal slices from rats given ethanol and MDMA, the CP 93,129-induced inhibition and methiotepin-induced facilitation of 5-HT release were stronger and weaker, respectively, than in the other groups. This is the first study addressing long-term effects of repeated MDMA and EtOH combined treatments in experimental animals. Whereas the drug combination produced the same behavioral and neurochemical effects as MDMA alone, our neuropharmacological results suggest that MDMA–EtOH interactions may have specific long-term consequences on presynaptic modulation of hippocampal 5-HT release, but not necessarily related to MDMA-induced depletion of 5-HT. Thus, it is likely that the psycho(patho)logical problems reported by ecstasy users drinking alcohol are not solely due to the consumption of MDMA.