Reduced efficacy of fluoxetine following MDMA ("Ecstasy")-induced serotonin loss in rats.
Sarah Durkin, Alison Prendergast, Andrew Harkin
Progress in neuro-psychopharmacology & biological psychiatry December 12, 2008 DOI: 10.1016/j.pnpbp.2008.09.008 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | MDMA Fluoxetine |
| Dose | MDMA 10 mg/kg i.p. four times daily for two days; fluoxetine 10 mg/kg i.p. (acute: 3 doses over 24h; chronic: once daily for 21 days) |
| Duration | 2-day MDMA exposure, 1-week washout, then acute (24h) or chronic (21 days) fluoxetine treatment |
| Measures | modified forced swimming test (FST), [3H]paroxetine binding, 5-HT and 5-HIAA levels |
| Topics | MDMA Serotonin |
| Key findings | Prior MDMA exposure attenuated fluoxetine-induced swimming behavior and serotonin metabolism reductions in rats, while MDMA itself caused long-term serotonin depletion. Chronic fluoxetine enhanced MDMA-induced serotonin loss, but this interaction vanished after drug elimination. The authors suggest fluoxetine may be less effective in treating depression among chronic MDMA users. |
Abstract
Long-term serotonin (5-HT) neuronal loss is currently a major cause of concern associated with recreational use of the substituted amphetamine 3,4 methylenedioxymethamphetamine (MDMA; "Ecstasy"). Such loss may be problematic considering that psychiatric disorders such as depression and anxiety and responses to first line treatments for these disorders are associated with 5-HT. In this study the effects of prior exposure to MDMA on behavioural and central neurochemical changes induced by the serotonin (5-HT) re-uptake inhibitor and antidepressant fluoxetine were examined in rats. Animals were administered MDMA (10 mg/kg. i.p.) four times daily for two consecutive days. One week later the animals were subjected to treatment with fluoxetine (10 mg/kg, i.p.). Fluoxetine treatment groups received either acute (saline injections for 20 days followed by 3 fluoxetine treatments over 24 h) or chronic (once daily fluoxetine for 21 days) drug administration. Prior exposure to MDMA resulted in an attenuation of fluoxetine-induced swimming behaviour in the modified forced swimming test (FST); a behavioural test of antidepressant action. In parallel MDMA treatment resulted in significant regional depletions of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) accompanied by a reduction in cortical [3H] paroxetine binding to nerve terminal 5-HT transporters. MDMA-induced 5-HT loss was enhanced in animals following chronic fluoxetine administration. Elimination of fluoxetine and its metabolite norfluoxetine from the brain abolished this interaction between MDMA and fluoxetine treatment. Fluoxetine administration reduced both 5-HIAA and the 5-HIAA:5-HT metabolism ratio, which was attenuated in animals pre-treated with MDMA. Overall the results show that MDMA induces long-term 5-HT loss in the rodent brain and consequently diminishes behaviour and reductions in 5-HT metabolism induced by the antidepressant fluoxetine. These results have potential clinical relevance, suggesting that 5-HT re-uptake inhibitors such as fluoxetine may be less effective at treating depression in chronic abusers of MDMA.