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

1. 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. 2. 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 [3H]-paroxetine binding 7 days later. 3. Fluoxetine (10 mg kg(-1), i.p., x2, 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., x2, 60 min apart) only produced neuroprotection when administered concurrently. Fluoxetine (10 mg kg(-1), x2) markedly increased the K(D) and reduced the B(max) of cortical [3H]-paroxetine binding 2 and 4 days later. The B(max) was still decreased 7 days later, but the K(D) was unchanged. [3H]-Paroxetine binding characteristics were unchanged 24 h after fluvoxamine (15 mg kg(-1), x2). 4. 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. 5. Pretreatment with fluoxetine (10 mg kg(-1), x2) failed to alter cerebral MDMA accumulation compared to saline pretreated controls. 6. Neither fluoxetine or fluvoxamine altered MDMA-induced acute hyperthermia. 7. 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.