The serotonergic antidepressant nefazodone inhibits the serotonin transporter: In vivo and ex vivo studies |
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| Affiliation: | 2. Laboratory of Neuropsychopharmacology, Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322;1. Medical Operations; Bristol-Myers Squibb; Plainsboro, New Jersey 08536 USA;1. Wuhan Docan Pharmaceutical Co., Ltd, Wuhan 430040, China;2. Pharmacy School of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;3. Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan 430060, China;1. Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, PR China;2. School of Engineering, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China;1. Laboratory of Pharmacology of Natural and Synthetic Products, Institute of Biological Sciences, Federal University of Goiás, Campus Samambaia, Goiânia, GO, Brazil;2. Laboratory of Medicinal Pharmaceutical Chemistry, Faculty of Pharmacy, Federal University of Goiás, Goiânia, GO, Brazil;3. Center for Biological and Health Sciences, Federal University of Western Bahia, Barreiras, BA, Brazil;4. Biochemical and Molecular Pharmacology Laboratory, Institute of Biological Sciences, Federal University of Goias, Campus Samambaia, Goiânia, GO, Brazil;1. Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland;2. Institute of Automatic Control, Silesian University of Technology, Gliwice, Poland;3. Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland;1. AntiCancer Inc., San Diego, CA, USA;2. Department of Surgery, University of California, San Diego, CA, USA;3. Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan;4. Basic Research Laboratory, National Cancer Institute, Frederick, MD, USA |
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| Abstract: | Nefazodone HCl (Serzone®) is a new antidepressant with a chemical structure unrelated to selective serotonin reuptake inhibitors (SSRIs), tricyclics, tetracyclics, or monoamine oxidase inhibitors (MAOIs). Nefazodone is active in a number of preclinical tests for antidepressant activity and shows clinical efficacy in the treatment of depression with a more favorable side-effect profile than the structurally similar antidepressant trazodone. Previous studies have shown that nefazodone is a potent antagonist of 5-HT2A receptors and binds to the serotonin transporter in vitro and in vivo. Nefazodone also binds to the norepinephrine transporter in vitro and in acute ex vivo studies. To further investigate the ability of nefazodone to modify serotonergic transmission, the ability of systemically administered nefazodone to inhibit the serotonin transporter was assessed by investigating the ability of nefazodone to prevent p-chloroamphetamine- (PCA) induced depletions of cortical 5-HT concentrations. In addition, the ability of acute and subchronic nefazodone administration to inhibit ex vivo [3H]-5-HT uptake was assessed. Acute administration of nefazodone (30, 100, and 150 mg/kg) antagonized PCA-induced depletion of cortical 5-HT concentrations in a dose-dependent manner at 1,2, and 3 hours post-treatment. This effect was directly correlated with serum nefazodone concentrations. Both 100 mg/kg and 150 mg/kg of nefazodone were equipotent with fluoxetine (10 mg/kg) over the course of the experiment with respect to sparing of 5-HT depletion. Acute administration of nefazodone (100 and 150 mg/kg s.c.) significantly increased the Km, for [3H]-5-HT uptake in rat cortical synaptosomes from 60 nmol/L in controls to 230 and 242 nmol/L in nefazodone-treated rats, respectively. Subchronic administration of nefazodone (100 and 150 mg/kg, s.c., b.i.d. × 5.5 days) reduced [3H]-5-HT uptake by 24% and 29%, respectively. Sub-chronic dosing with fluoxetine (5 mg/kg, s.c., b.i.d. × 5.5 days) reduced [3H]-5-HT uptake by 65% These experiments confirm and extend previous reports concerning the ability of nefazodone to inhibit the 5-HT transporter in vivo. |
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