2004 IRISH SCIENTIST YEAR BOOK

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University College Cork & Trinity College Dublin
Andrew Harkin & Thomas Connor
Abuse of 'Ecstasy': a predisposing factor to depression?

Methylenedioxymethamphetamine (MDMA; 'Ecstasy') is a recreational drug and, according to a recent United Nations Global Drug Survey, Ireland is amongst those European countries showing an increased prevalence of MDMA abuse. Whilst the incidence of acute toxicity and fatalities associated with MDMA consumption is relatively low, long-term neurotoxicity is a major cause of concern. Specifically, a vast literature indicates that MDMA produces serotonergic nerve terminal loss in the central nervous system (CNS) of both laboratory animals, and humans. Serotonergic neurodegeneration induced by MDMA is problematic, considering that psychiatric disorders such as depression and panic disorder are associated with low serotonin. In addition, a number of case reports indicate that users of drugs that elicit serotonergic neurotoxicity, such as MDMA, have presented with psychiatric symptoms including depression and panic attacks.


A schematic diagram outlining the action of SSRIs at a normal serotonin nerve terminal, the impaired action of an SSRI at a serotonin nerve terminal damaged by MDMA, and the possibility that regeneration of nerve terminals by BDNF may restore antidepressant efficacy

Selective serotonin reuptake inhibitors (SSRIs) are at present the first line choice in the treatment of depression, and anxiety states such as panic disorder. The ability of these drugs to block pre-synaptic serotonin transporter sites underlies their therapeutic action: however, a hallmark of chronic administration of MDMA is a reduction in the number of serotonin transporter sites in the CNS. We have previously demonstrated that both MDMA, and its metabolite MDA, produce serotonin nerve terminal loss that results in resistance to the prototypical SSRI fluoxetine (Prozac�), in behavioural and neurochemical tests predictive of antidepressant efficacy. These data suggest that SSRIs may be less effective in treating depression that occurs following abuse of MDMA.

Current research is focused on examining the possibility that antidepressant responses can be reinstated, following spontaneous regeneration of serotonin nerve terminals that occurs slowly over time. In addition, it is suggested that strategies that promote regeneration of serotonin nerve terminals will accelerate and enhance recovery of antidepressant action following exposure to MDMA. For instance, exogenous administration of brain-derived neurotrophic factor (BDNF), or strategies that enhance endogenous BDNF expression, are being examined with a view to promoting serotonin nerve terminal regeneration, and reinstatement of antidepressant responsiveness. These studies will enhance our understanding of the ability of the brain to recover from MDMA induced serotonergic neurotoxicity.

Contact: Dr Andrew Harkin, Department of Pharmacology & Therapeutics, School of Pharmacy, University College Cork;
E-mail: [email protected]