The present project is aimed at obtaining fundamental knowledge of the mechanisms of Ecstasy (3,4-methylenedioxymethamphetamine: MDMA) action(s) in the CNS. The overall strategy will be an investigation into both short and long-term effects of MDMA namely its immediate neurophysiological and behavioural effects and its neurotoxicity, causing neurodegeneration and subsequent adaptive/repair changes in brain. The goal is to gain increased insight into the mode(s) of action of MDMA and chemically related drugs, and provide new clues to the pathophysiology of MDMA-induced damage, with the aim of defining more precisely the targets involved. This should allow identification of molecular targets for designing new pharmacological compounds and/or therapeutic strategies to reduce/prevent the disorders arising from exposure to MDMA.

In the course of the project, a novel animal model of MDMA-induced lesion, likely to represent that occurring in occasional human consumers, will be fully characterised and evaluated in comparison with the previously available model of severe MDMA lesion.

The immediate actions of MDMA related to neurotoxicity will be studied, focussing on changes in 5-HT receptor regional expression, cell recycling rate, transduction cascade(s) etc., using multidisciplinary approaches including the use of several genetically modified (5-HT receptor or 5-HT re-uptake transporter k.o.) mice.

The long-term functional and cerebrovascular consequences of exposure to MDMA in adolescence, as well as the role of 5-HT systems in the functional organization of the brain during periods of depletion and regrowth will be studied. A long-term study of changes in brain metabolism (glucose metabolism and cerebral blood flow), EEG activity, sleep, and behaviour with special focus on the dynamic phases of acute damage and repair/re-innervation will be realised. The investigation will address the changes in 5-HT receptor sensitivity, expression, and distribution in the CNS and the sensitivity of MDMA lesioned rats to 5-HT receptor agonists (including anxiolytic agents) and/or antidepressant drugs.

The behavioural, neurochemical and neurophysiological correlates relevant to the immediate cognitive deficits produced by MDMA will be investigated. The study will address the immediate and long-term consequences of MDMA lesion on cognitive performances in rats, and the transcription factors (e.g. CREB) and related phosphorylating enzymes (e.g. MAPKs) possibly involved in the immediate and persistent cognitive deficits.

The overall achievement of this project will be the identification of the actual role of serotonin in the pathophysiology of brain damage produced by MDMA abuse.