The acute and long-term effects of 3,4- methylenedioxymethamphetamine (MDMA; 'ecstasy') upon cerebral and cerebrovascular serotonergic processes.
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Ferrington, L. (2004) The acute and long-term effects of 3, 4- methylenedioxymethamphetamine (MDMA; 'ecstasy') upon cerebral and cerebrovascular serotonergic processes., no. 361.
The amphetamine derivative 3,4,-methylenedioxymethamphetamine (MDMA; Ecstasy) is a recreational drug of abuse, particularly popular among young people with whom it has formed a well-established sub-culture. MDMA is popular for its euphoria-inducing and mild stimulant properties and its popularity continues to rise despite a number of well-publicised cases of MDMA-associated fatalities and evidence of MDMA-induced acute toxicity. MDMA is known to produce an acute efflux of serotonin (5-HT) release in the brains of experimental animals, in which a marked behavioural response is also demonstrated. In the long-term MDMA causes specific neurotoxic damage to serotonergic nerve terminals, a phenomenon which is not demonstrated in other neurotransmitters. MDMA use has been associated with long-term adverse effects on both psychological and physiological health and this may represent a major public health problem given the 2 million people who use the drug in the UK alone. However, there is a perceived imbalance between the relative number of those who use MDMA and the serious adverse effects of the drug and it is possible that these may occur in a more susceptible sub-population of users. This thesis involves in vivo work using the Dark Agouti (DA) rat strain which is known to be more susceptible to MDMA and which may therefore provide an insight in this more susceptible sub-population of human MDMA users. The data presented in this thesis demonstrate that a single exposure to MDMA (15mg.kg-1) has a significal effect upon local cerebral glucose utilisation (LCMRglu) and local cerebral blood flow (LCBF) in DA rats both acutely and in the longer-term. This work demonstrates that this single dose of MDMA is neurotoxic to serotonergic neurons, inducing up to 80% depletion of serotonergic nerve terminals 6 weeks later. Furthermore, data generated from pharmacological challenges upon animals treated with MDMA 6 weeks earlier demonstrates the existence of compensatory mechanisms which act to normalise LCMRglu and LCBF, despite the persistence of serotonergic depletion. Thus this thesis extends the currently available information regarding acute and long-term effects of MDMA in a vulnerable sub-population of users and also proposes potential theories for the mechanisms of action by which pharmacological compensation for these long-term effects of MDMA-induced neurotoxicity may occur. In addition this thesis examines the effects of previous exposure to MDMA upon physiological challenges that might realistically be encountered by human users of the drug. The nature of MDMA-induced neurotoxicity suggests that human users of MDMA may suffer from untreatable chronic psychosis, and this thesis lends support to the view that currently available first line anti-depressant therapies may not be useful in the treatment of this sub-section of the population.