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Reduced efficacy of fluoxetine following MDMA ("Ecstasy")-induced serotonin loss in rats.

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.

Authors+Show Affiliations

Trinity College Institute of Neuroscience, School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18824064

Citation

Durkin, Sarah, et al. "Reduced Efficacy of Fluoxetine Following MDMA ("Ecstasy")-induced Serotonin Loss in Rats." Progress in Neuro-psychopharmacology & Biological Psychiatry, vol. 32, no. 8, 2008, pp. 1894-901.
Durkin S, Prendergast A, Harkin A. Reduced efficacy of fluoxetine following MDMA ("Ecstasy")-induced serotonin loss in rats. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(8):1894-901.
Durkin, S., Prendergast, A., & Harkin, A. (2008). Reduced efficacy of fluoxetine following MDMA ("Ecstasy")-induced serotonin loss in rats. Progress in Neuro-psychopharmacology & Biological Psychiatry, 32(8), pp. 1894-901. doi:10.1016/j.pnpbp.2008.09.008.
Durkin S, Prendergast A, Harkin A. Reduced Efficacy of Fluoxetine Following MDMA ("Ecstasy")-induced Serotonin Loss in Rats. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Dec 12;32(8):1894-901. PubMed PMID: 18824064.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reduced efficacy of fluoxetine following MDMA ("Ecstasy")-induced serotonin loss in rats. AU - Durkin,Sarah, AU - Prendergast,Alison, AU - Harkin,Andrew, Y1 - 2008/09/13/ PY - 2008/06/20/received PY - 2008/09/03/revised PY - 2008/09/03/accepted PY - 2008/10/1/pubmed PY - 2009/4/16/medline PY - 2008/10/1/entrez SP - 1894 EP - 901 JF - Progress in neuro-psychopharmacology & biological psychiatry JO - Prog. Neuropsychopharmacol. Biol. Psychiatry VL - 32 IS - 8 N2 - 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. SN - 0278-5846 UR - https://www.unboundmedicine.com/medline/citation/18824064/Reduced_efficacy_of_fluoxetine_following_MDMA__"Ecstasy"__induced_serotonin_loss_in_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0278-5846(08)00279-0 DB - PRIME DP - Unbound Medicine ER -