title: Methylenendioxyamphetamine produces serotonin nerve terminal loss and diminished behavioural and neurochemical responses to the antidepressant fluoxetine.
abstract: The effect of prior exposure to methylenedioxyamphetamine (MDA) on behavioural and neurochemical responses to fluoxetine were assessed in a rat model of antidepressant action. MDA (7.5 mg/kg, i.p.) was administered to rats twice daily for 4 consecutive days, and 4 weeks later the behavioural effect of fluoxetine (5 or 20 mg/kg; i.p. x 3) was examined in the modified rat forced-swimming test. In addition, the ability of fluoxetine to reduce serotonin (5-HT) metabolism was measured as an index of its efficacy in inhibiting 5-HT reuptake in vivo. In vehicle-treated rats, fluoxetine (5 and 20 mg/kg) produced a characteristic increase in swimming behaviour in the forced-swimming test. In contrast, fluoxetine-induced swimming was markedly attenuated in MDA-treated rats. MDA pretreatment resulted in 5-HT nerve terminal degeneration, indicated by reduced 5-HT and 5-HIAA concentrations in the frontal cortex, amygdala and hippocampus, and reduced [3H]paroxetine binding in the frontal cortex. In vehicle-treated rats, fluoxetine (5 and 20 mg/kg) decreased 5-HT metabolism (5-HIAA : 5-HT ratio) in the frontal cortex, amygdala and hippocampus. MDA pretreatment attenuated the ability of fluoxetine to reduce 5-HT metabolism in all brain regions examined. These findings are the first to demonstrate that prior exposure to the methylenedioxy-substituted amphetamine MDA results in diminished responsiveness to the antidepressant fluoxetine.
authors.affiliation: Department of Pharmacology, National University of Ireland, Galway, Ireland.
authors.forename: Andrew
authors.initials: A
authors.lastname: Harkin
authors.forename: Eamonn
authors.initials: E
authors.lastname: Shanahan
authors.forename: John P
authors.initials: JP
authors.lastname: Kelly
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Connor
mesh_terms: D015104:3,4-Methylenedioxyamphetamine / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D005473:Fluoxetine / Q000494:pharmacology; D006213:Hallucinogens / Q000494:pharmacology*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D017374:Paroxetine / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D006213:Hallucinogens; D005473:Fluoxetine; D012701:Serotonin; D017374:Paroxetine; D015104:3,4-Methylenedioxyamphetamine; D006897:Hydroxyindoleacetic Acid