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.
Sanchez
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Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Madrid 28040, Spain. Pharmacology Research Group, School of Pharmacy, De Montfort University, Leicester LE1 9BH. AstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE11 5RH.
Camarero
J
J
Esteban
B
B
Peter
M J
MJ
Green
A R
AR
Colado
M I
MI
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism; D005473:Fluoxetine / Q000378:metabolism / Q000494:pharmacology*; D016666:Fluvoxamine / Q000494:pharmacology; D007211:Indoles / Q000378:metabolism; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000008:administration & dosage* / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000517:prevention & control*; D009411:Nerve Endings / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017374:Paroxetine / Q000378:metabolism; D051381:Rats; D012007:Rectum / Q000502:physiology; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000494:pharmacology; D013997:Time Factors; D014316:Tritium
D007211:Indoles; D018696:Neuroprotective Agents; D018490:Serotonin Agents; D005473:Fluoxetine; D014316:Tritium; D012701:Serotonin; D017374:Paroxetine; C030374:indole; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D016666:Fluvoxamine