RATIONALE: Fluoxetine is used to treat unipolar depression and is thought to act by increasing the concentration of serotonin (5-HT) in the synaptic cleft, leading to increased serotonin signaling. The 5-HT(2A/2C) receptor subtypes are coupled to a phospholipase A(2) (PLA(2)). We hypothesized that chronic fluoxetine would increase the brain activity of PLA(2) and the turnover rate of arachidonic acid (AA) in phospholipids of the unanesthetized rat. MATERIALS AND METHODS: To test this hypothesis, rats were administered fluoxetine (10 mg/kg) or vehicle intraperitoneally daily for 21 days. In the unanesthetized rat, [1-(14)C]AA was infused intravenously and arterial blood plasma was sampled until the animal was killed at 5 min and its brain was subjected to chemical, radiotracer, or enzyme analysis. RESULTS: Using equations from our fatty acid model, we found that chronic fluoxetine compared with vehicle increased the turnover rate of AA within several brain phospholipids by 75-86%. The activity and protein levels of brain cytosolic PLA(2) (cPLA(2)) but not of secretory or calcium-independent PLA(2) were increased in rats administered fluoxetine. In a separate group of animals that received chronic fluoxetine followed by a 3-day saline washout, the turnover of AA and activity and protein levels of cPLA(2) were not significantly different from controls. The protein levels of cyclooxygenases 1 and 2 as well as the concentration of prostaglandin E(2) in rats chronically administered fluoxetine did not differ significantly from controls. CONCLUSION: The results support the hypothesis that fluoxetine increases the cPLA(2)-mediated turnover of AA within brain phospholipids.
RATIONALE: Fluoxetine is used to treat unipolar depression and is thought to act by increasing the concentration of serotonin (5-HT) in the synaptic cleft, leading to increased serotonin signaling. The 5-HT(2A/2C) receptor subtypes are coupled to a phospholipase A(2) (PLA(2)). We hypothesized that chronic fluoxetine would increase the brain activity of PLA(2) and the turnover rate of arachidonic acid (AA) in phospholipids of the unanesthetized rat. MATERIALS AND METHODS: To test this hypothesis, rats were administered fluoxetine (10 mg/kg) or vehicle intraperitoneally daily for 21 days. In the unanesthetized rat, [1-(14)C]AA was infused intravenously and arterial blood plasma was sampled until the animal was killed at 5 min and its brain was subjected to chemical, radiotracer, or enzyme analysis. RESULTS: Using equations from our fatty acid model, we found that chronic fluoxetine compared with vehicle increased the turnover rate of AA within several brain phospholipids by 75-86%. The activity and protein levels of brain cytosolic PLA(2) (cPLA(2)) but not of secretory or calcium-independent PLA(2) were increased in rats administered fluoxetine. In a separate group of animals that received chronic fluoxetine followed by a 3-day saline washout, the turnover of AA and activity and protein levels of cPLA(2) were not significantly different from controls. The protein levels of cyclooxygenases 1 and 2 as well as the concentration of prostaglandin E(2) in rats chronically administered fluoxetine did not differ significantly from controls. CONCLUSION: The results support the hypothesis that fluoxetine increases the cPLA(2)-mediated turnover of AA within brain phospholipids.
Authors: K J Damjanoska; L D Van de Kar; G H Kindel; Y Zhang; D N D'Souza; F Garcia; G Battaglia; N A Muma Journal: J Pharmacol Exp Ther Date: 2003-04-29 Impact factor: 4.030
Authors: Epolia Ramadan; Lisa Chang; Mei Chen; Kaizong Ma; F Scott Hall; George R Uhl; Stanley I Rapoport; Mireille Basselin Journal: Int J Neurosci Date: 2012-03-26 Impact factor: 2.292
Authors: Yewon Cheon; Jee-Young Park; Hiren R Modi; Hyung-Wook Kim; Ho-Joo Lee; Lisa Chang; Jagadeesh S Rao; Stanley I Rapoport Journal: J Neurochem Date: 2011-09-20 Impact factor: 5.372
Authors: Mireille Basselin; Meredith A Fox; Lisa Chang; Jane M Bell; Dede Greenstein; Mei Chen; Dennis L Murphy; Stanley I Rapoport Journal: Neuropsychopharmacology Date: 2009-01-14 Impact factor: 7.853