The mechanisms involved in the long‐lasting neuroprotective effect of fluoxetine against MDMA (‘ecstasy’)‐induced degeneration of 5‐HT nerve endings in rat brain
Violeta Sánchez Sánchez, Jorge Camarero, B. Moreno Esteban, Markus Peter, A R Green, María Isabel Colado
British Journal of Pharmacology September 1, 2001 DOI: 10.1038/sj.bjp.0704230 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | Fluoxetine Fluvoxamine MDMA |
| Dose | MDMA 15 mg/kg i.p.; Fluoxetine 10 mg/kg i.p. ×2, 60 min apart; Fluvoxamine 15 mg/kg i.p. ×2, 60 min apart |
| Duration | 7 days post-MDMA |
| Topics | MDMA Serotonin |
| Keywords | Fluoxetine Paroxetine Fluvoxamine Pharmacology Neurotoxicity Neuroprotection Hippocampus Antidepressant Endocrinology Anesthesia |
| Citations | 103 |
| Key findings | Fluoxetine, but not fluvoxamine, provides long-lasting protection against MDMA-induced neurodegeneration by inhibiting the serotonin transporter without altering MDMA accumulation or metabolism. |
Abstract
It has been reported that co‐administration of fluoxetine with 3,4‐methylenedioxymethamphetamine (MDMA, ‘ecstasy’) prevents MDMA‐induced degeneration of 5‐HT nerve endings in rat brain. The mechanisms involved have now been investigated. MDMA (15 mg kg −1 , i.p.) administration produced a neurotoxic loss of 5‐HT and 5‐hydroxyindoleacetic acid (5‐HIAA) in cortex, hippocampus and striatum and a reduction in cortical [ 3 H]‐paroxetine binding 7 days later. Fluoxetine (10 mg kg −1 , i.p., ×2, 60 min apart) administered concurrently with MDMA or given 2 and 4 days earlier provided complete protection, and significant protection when given 7 days earlier. Fluvoxamine (15 mg kg −1 , i.p., ×2, 60 min apart) only produced neuroprotection when administered concurrently. Fluoxetine (10 mg kg −1 , ×2) markedly increased the K D and reduced the B max of cortical [ 3 H]‐paroxetine binding 2 and 4 days later. The B max was still decreased 7 days later, but the K D was unchanged. [ 3 H]‐Paroxetine binding characteristics were unchanged 24 h after fluvoxamine (15 mg kg −1 , ×2). A significant cerebral concentration of fluoxetine plus norfluoxetine was detected over the 7 days following fluoxetine administration. The fluvoxamine concentration had decreased markedly by 24 h. Pretreatment with fluoxetine (10 mg kg −1 , ×2) failed to alter cerebral MDMA accumulation compared to saline pretreated controls. Neither fluoxetine or fluvoxamine altered MDMA‐induced acute hyperthermia. These data demonstrate that fluoxetine produces long‐lasting protection against MDMA‐induced neurodegeneration, an effect apparently related to the presence of the drug and its active metabolite inhibiting the 5‐HT transporter. Fluoxetine does not alter the metabolism of MDMA or its rate of cerebral accumulation. British Journal of Pharmacology (2001) 134 , 46–57; doi: 10.1038/sj.bjp.0704230
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 34
- The pharmacology of the acute hyperthermic response that follows administration of 3,4‐methylenedioxymethamphetamine (MDMA, ‘ecstasy’) to rats British Journal of Pharmacology 2002
- The Role of Metabolism in 3,4-(±)-Methylenedioxyamphetamine and 3,4-(±)-Methylenedioxymethamphetamine (Ecstasy) toxicity Therapeutic Drug Monitoring March 19, 2004
- MDMA self‐administration in rats: acquisition, progressive ratio responding and serotonin transporter binding European Journal of Neuroscience November 16, 2007
- Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine ACS Chemical Neuroscience July 12, 2018
- Qualitative Review of Serotonin Syndrome, Ecstasy (MDMA) and the use of Other Serotonergic Substances: Hierarchy of Risk Australian & New Zealand Journal of Psychiatry July 25, 2007
and 29 more in the library
Cites 29
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- The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Proceedings of the National Academy of Sciences March 1, 1992
- Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Journal of Pharmacology and Experimental Therapeutics 1987
- Neurotoxicity of MDMA and Related Compounds: Anatomic Studiesa Annals of the New York Academy of Sciences October 1, 1990
- Carrier‐Mediated Release of Serotonin by 3,4‐Methylenedioxymethamphetamine: Implications for Serotonin‐Dopamine Interactions Journal of Neurochemistry 1996
and 24 more in the library