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Sanchez V, Camarero J, Esteban B, Peter MJ, Green AR, Colado MI. 
“The mechanisms involved in the long-lasting neuroprotective effect of fluoxetine against MDMA ('ecstasy')-induced degeneration of 5-HT nerve endings in rat brain”. 
Br J Pharmacol. 2001 Sep;134(1):46-57.
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 [(3)H]-paroxetine binding 7 days later. 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.

3. Fluoxetine (10 mg kg(-1), x2) 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), 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.
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