Alterations in brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in the brain regions of a learned helplessness rat model and the antidepressant effects of a TrkB agonist and antagonist

Eur Neuropsychopharmacol. 2015 Dec;25(12):2449-58. doi: 10.1016/j.euroneuro.2015.09.002. Epub 2015 Sep 9.


Role of brain-derived neurotrophic factor (BDNF)-TrkB signaling in a learned helplessness (LH) model of depression was investigated. LH rats showed a reduction of BDNF in the medial prefrontal cortex (mPFC), CA3, and dentate gyrus (DG) of the hippocampus, whereas LH rats showed an increase in BDNF in the nucleus accumbens (NAc). Furthermore, levels of proBDNF, a BDNF precursor, were higher in the mPFC, but lower in the NAc, of LH rats. A single bilateral infusion of a TrkB agonist 7,8-DHF, but not a TrkB antagonist ANA-12, into the infralimbic (IL) of mPFC, DG, and CA3, but not the prelimbic (PrL) of mPFC, exerted antidepressant effects in LH rats. In contrast, a single bilateral infusion of ANA-12, but not 7,8-DHF, into the core and shell of NAc exerted antidepressant-like effects in LH rats, with more potent effects observed for the NAc core than for NAc shell. Interestingly, a single administration of 7,8-DHF (10mg/kg, i.p.) significantly improved a decreased phosphorylation of TrkB in the mPFC, CA3, and DG of LH rats. Additionally, ANA-12 (0.5mg/kg, i.p.) significantly improved an increased phosphorylation of TrkB in the NAc of LH rats. In conclusion, these results suggest that LH causes depression-like behavior by altering BDNF in the brain regions, and that proBDNF-BDNF processing and transport may be altered in the mPFC-NAc circuit of LH rats. Therefore, TrkB agonists might exert antidepressant effects by stimulating TrkB in the IL, CA3, and DG, while TrkB antagonists might exert antidepressant effects by blocking TrkB in the NAc.

Keywords: Brain-derived neurotrophic factor; Hippocampus; Infralimbic cortex; Nucleus accumbens; Prelimbic cortex; proBDNF.

MeSH terms

  • Analysis of Variance
  • Animals
  • Antidepressive Agents / pharmacology*
  • Azepines / pharmacology
  • Benzamides / pharmacology
  • Brain / drug effects
  • Brain / metabolism*
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Flavones / pharmacology
  • Helplessness, Learned*
  • Male
  • Protein Precursors / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, trkB / agonists
  • Receptor, trkB / antagonists & inhibitors
  • Receptor, trkB / metabolism
  • Stress, Psychological / drug therapy
  • Stress, Psychological / metabolism
  • Time Factors


  • 6,7-dihydroxyflavone
  • ANA 12 compound
  • Antidepressive Agents
  • Azepines
  • Benzamides
  • Brain-Derived Neurotrophic Factor
  • Flavones
  • Protein Precursors
  • brain-derived neurotrophic factor precursor
  • Receptor, trkB