title: Transient postnatal fluoxetine leads to decreased brain arachidonic acid metabolism and cytochrome P450 4A in adult mice.
abstract: Fetal and perinatal exposure to selective serotonin (5-HT) reuptake inhibitors (SSRIs) has been reported to alter childhood behavior, while transient early exposure in rodents is reported to alter their behavior and decrease brain extracellular 5-HT in adulthood. Since 5-HT2A/2C receptor-mediated neurotransmission can involve G-protein coupled activation of cytosolic phospholipase A2 (cPLA2), releasing arachidonic acid (ARA) from synaptic membrane phospholipid, we hypothesized that transient postnatal exposure to fluoxetine would alter brain ARA metabolism in adult mice. Brain ARA incorporation coefficients k* and rates Jin were quantitatively imaged following intravenous [1-(14)C]ARA infusion of unanesthetized adult mice that had been injected daily with fluoxetine (10mg/kg i.p.) or saline during postnatal days P4-P21. Expression of brain ARA metabolic enzymes and other relevant markers also was measured. On neuroimaging, k* and Jin was decreased widely in early fluoxetine- compared to saline-treated adult mice. Of the enzymes measured, cPLA2 activity was unchanged, while Ca(2+)-independent iPLA2 activity was increased. There was a significant 74% reduced protein level of cytochrome P450 (CYP) 4A, which can convert ARA to 20-HETE. Reduced brain ARA metabolism in adult mice transiently exposed to postnatal fluoxetine, and a 74% reduction in CYP4A protein, suggest long-term effects independent of drug presence in brain ARA metabolism, and in CYP4A metabolites. These changes might contribute to reported altered behavior following early SSRI in rodents.
authors: Brain Physiology and Metabolism Section, Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors: Epolia
authors: E
authors: Ramadan
authors: Brain Physiology and Metabolism Section, Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors: Helene
authors: H
authors: Blanchard
authors: Brain Physiology and Metabolism Section, Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors: Yewon
authors: Y
authors: Cheon
authors: Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Meredith A
authors: MA
authors: Fox
authors: Brain Physiology and Metabolism Section, Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors: Lisa
authors: L
authors: Chang
authors: Brain Physiology and Metabolism Section, Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors: Mei
authors: M
authors: Chen
authors: Brain Physiology and Metabolism Section, Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors: Kaizong
authors: K
authors: Ma
authors: Brain Physiology and Metabolism Section, Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors: Stanley I
authors: SI
authors: Rapoport
authors: Brain Physiology and Metabolism Section, Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. Electronic address: mirvasln@mail.nih.gov.
authors: Mireille
authors: M
authors: Basselin
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D042926:Cytochrome P-450 CYP4A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005473:Fluoxetine / Q000009:adverse effects* / Q000494:pharmacology; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D016718:Arachidonic Acid; D002118:Calcium; D042926:Cytochrome P-450 CYP4A; D005473:Fluoxetine; D009419:Nerve Tissue Proteins; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Arachidonic acid; Brain; Cytochrome P450 4A; Fluoxetine; Metabolism; Mouse; Neurodevelopment; Neuroimaging; Postnatal; SSRI; Serotonin