title: Transcriptional evidence for the role of chronic venlafaxine treatment in neurotrophic signaling and neuroplasticity including also Glutamatergic [corrected] - and insulin-mediated neuronal processes.
abstract: OBJECTIVE
  Venlafaxine (VLX), a serotonine-noradrenaline reuptake inhibitor, is one of the most commonly used antidepressant drugs in clinical practice for the treatment of major depressive disorder (MDD). Despite being more potent than its predecessors, similarly to them, the therapeutical effect of VLX is visible only 3-4 weeks after the beginning of treatment. Furthermore, recent papers show that antidepressants, including also VLX, enhance the motor recovery after stroke even in non depressed persons. In the present, transcriptomic-based study we looked for changes in gene expressions after a long-term VLX administration.
  
  
  METHODS
  Osmotic minipumps were implanted subcutaneously into Dark Agouti rats providing a continuous (40 mg/kg/day) VLX delivery for three weeks. Frontal regions of the cerebral cortex were isolated and analyzed using Illumina bead arrays to detect genes showing significant chances in expression. Gene set enrichment analysis was performed to identify specific regulatory networks significantly affected by long term VLX treatment.
  
  
  RESULTS
  Chronic VLX administration may have an effect on neurotransmitter release via the regulation of genes involved in vesicular exocytosis and receptor endocytosis (such as Kif proteins, Myo5a, Sv2b, Syn2 or Synj2). Simultaneously, VLX activated the expression of genes involved in neurotrophic signaling (Ntrk2, Ntrk3), glutamatergic transmission (Gria3, Grin2b and Grin2a), neuroplasticity (Camk2g/b, Cd47), synaptogenesis (Epha5a, Gad2) and cognitive processes (Clstn2). Interestingly, VLX increased the expression of genes involved in mitochondrial antioxidant activity (Bcl2 and Prdx1). Additionally, VLX administration also modulated genes related to insulin signaling pathway (Negr1, Ppp3r1, Slc2a4 and Enpp1), a mechanism that has recently been linked to neuroprotection, learning and memory.
  
  
  CONCLUSIONS
  Our results strongly suggest that chronic VLX treatment improves functional reorganization and brain plasticity by influencing gene expression in regulatory networks of motor cortical areas. These results are consonant with the synaptic (network) hypothesis of depression and antidepressant-induced motor recovery after stroke.
authors.affiliation: Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary; MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Budapest, Hungary.
authors.forename: Viola
authors.initials: V
authors.lastname: Tamási
authors.affiliation: Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary; MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Budapest, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Petschner
authors.affiliation: Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary; Department of Neuroscience, Karoliska Institutet, Stockholm, Sweden.
authors.forename: Csaba
authors.initials: C
authors.lastname: Adori
authors.affiliation: Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary.
authors.forename: Eszter
authors.initials: E
authors.lastname: Kirilly
authors.affiliation: Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary.
authors.forename: Romeo D
authors.initials: RD
authors.lastname: Ando
authors.affiliation: Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Tothfalusi
authors.affiliation: Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary; MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Budapest, Hungary; Neuroscience and Psychiatry Unit, University of Manchester, Manchester, United Kingdom.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Juhasz
authors.affiliation: Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary; MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Budapest, Hungary.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Bagdy
mesh_terms: D000818:Animals; D020869:Gene Expression Profiling; D005971:Glutamates / Q000502:physiology*; D007328:Insulin / Q000502:physiology*; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic; D000069470:Venlafaxine Hydrochloride / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D005971:Glutamates; D007328:Insulin; D012333:RNA, Messenger; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride