The mechanisms involved in the long‐lasting neuroprotective effect of fluoxetine against MDMA (‘ecstasy’)‐induced degeneration of 5‐HT nerve endings in rat brain

Fluoxetine provides long-lasting protection against MDMA-induced damage to serotonin nerve endings in rat brain, while fluvoxamine only protects when given at the same time. MDMA caused loss of serotonin and its metabolite in cortex, hippocampus, and striatum, and reduced paroxetine binding one week later. Fluoxetine given with MDMA or up to four days before offered complete protection, and significant protection when given seven days before. Fluvoxamine required concurrent administration. Fluoxetine's protection appears due to its and its active metabolite's inhibition of the serotonin transporter, not by altering MDMA accumulation or metabolism.

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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