title: Antidepressant drugs transactivate TrkB neurotrophin receptors in the adult rodent brain independently of BDNF and monoamine transporter blockade.
abstract: BACKGROUND
  Antidepressant drugs (ADs) have been shown to activate BDNF (brain-derived neurotrophic factor) receptor TrkB in the rodent brain but the mechanism underlying this phenomenon remains unclear. ADs act as monoamine reuptake inhibitors and after prolonged treatments regulate brain bdnf mRNA levels indicating that monoamine-BDNF signaling regulate AD-induced TrkB activation in vivo. However, recent findings demonstrate that Trk receptors can be transactivated independently of their neurotrophin ligands.
  
  
  METHODS
  In this study we examined the role of BDNF, TrkB kinase activity and monoamine reuptake in the AD-induced TrkB activation in vivo and in vitro by employing several transgenic mouse models, cultured neurons and TrkB-expressing cell lines.
  
  
  RESULTS
  Using a chemical-genetic TrkB(F616A) mutant and TrkB overexpressing mice, we demonstrate that ADs specifically activate both the maturely and immaturely glycosylated forms of TrkB receptors in the brain in a TrkB kinase dependent manner. However, the tricyclic AD imipramine readily induced the phosphorylation of TrkB receptors in conditional bdnf⁻/⁻ knock-out mice (132.4±8.5% of control; P = 0.01), indicating that BDNF is not required for the TrkB activation. Moreover, using serotonin transporter (SERT) deficient mice and chemical lesions of monoaminergic neurons we show that neither a functional SERT nor monoamines are required for the TrkB phosphorylation response induced by the serotonin selective reuptake inhibitors fluoxetine or citalopram, or norepinephrine selective reuptake inhibitor reboxetine. However, neither ADs nor monoamine transmitters activated TrkB in cultured neurons or cell lines expressing TrkB receptors, arguing that ADs do not directly bind to TrkB.
  
  
  CONCLUSIONS
  The present findings suggest that ADs transactivate brain TrkB receptors independently of BDNF and monoamine reuptake blockade and emphasize the need of an intact tissue context for the ability of ADs to induce TrkB activity in brain.
authors.affiliation: Sigrid Jusélius Laboratory, Neuroscience Center, University of Helsinki, Helsinki, Finland. tomi.rantamaki@helsinki.fi
authors.forename: Tomi
authors.initials: T
authors.lastname: Rantamäki
authors.forename: Liisa
authors.initials: L
authors.lastname: Vesa
authors.forename: Hanna
authors.initials: H
authors.lastname: Antila
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Lieto
authors.forename: Päivi
authors.initials: P
authors.lastname: Tammela
authors.forename: Angelika
authors.initials: A
authors.lastname: Schmitt
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.forename: Maribel
authors.initials: M
authors.lastname: Rios
authors.forename: Eero
authors.initials: E
authors.lastname: Castrén
mesh_terms: D000375:Aging / Q000187:drug effects*; D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D006031:Glycosylation / Q000187:drug effects; D007099:Imipramine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D020813:Receptor, trkB / Q000235:genetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects* / Q000235:genetics; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D050486:Serotonin Plasma Membrane Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D000639:Amitriptyline; D020813:Receptor, trkB; D007099:Imipramine