title: An HDAC-dependent epigenetic mechanism that enhances the efficacy of the antidepressant drug fluoxetine.
abstract: Depression is a prevalent and debilitating psychiatric illnesses. However, currently prescribed antidepressant drugs are only efficacious in a limited group of patients. Studies on Balb/c mice suggested that histone deacetylase (HDAC) inhibition may enhance the efficacy of the widely-prescribed antidepressant drug fluoxetine. This study shows that reducing HDAC activity in fluoxetine-treated Balb/c mice leads to robust antidepressant and anxiolytic effects. While reducing the activity of class I HDACs 1 and 3 led to antidepressant effects, additional class II HDAC inhibition was necessary to exert anxiolytic effects. In fluoxetine-treated mice, HDAC inhibitors increased enrichment of acetylated histone H4 protein and RNA polymerase II at promotor 3 of the brain-derived neurotrophic factor (Bdnf) gene and increased Bdnf transcription from this promotor. Reducing Bdnf-stimulated tropomyosin kinase B receptor activation in fluoxetine-treated mice with low HDAC activity abolished the behavioral effects of fluoxetine, suggesting that the HDAC-triggered epigenetic stimulation of Bdnf expression is critical for therapeutic efficacy.
authors: 1] Department of Psychiatry, Columbia University, New York, NY 10032 [2] Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032.
authors: C
authors: C
authors: Schmauss
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism; D020813:Receptor, trkB; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D008562:Membrane Glycoproteins; D005473:Fluoxetine; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human; D012319:RNA Polymerase II; D006655:Histone Deacetylases
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