Enhanced BDNF Signaling is Associated with an Antidepressant-like Behavioral Response and Changes in Brain Monoamines

Abstract

1. Neurotrophins and serotonin have both been implicated in the pathophysiology of depression and in the mechanisms of antidepressant treatments. 2. Brain-derived neurotrophic factor (BDNF) influences the growth and plasticity of serotonergic (5-HT) neurons via the activation of trkB receptor. 3. Transgenic mice overexpressing the full-length trkB receptor (TrkB.TK+) and showing increased trkB activity in brain, and their wild type (WT) littermates, were injected with the antidepressant fluoxetine or saline, and analyzed behaviorally in the forced swimming test paradigm and biochemically for the concentrations of brain monoamines and their metabolites. 4. The TrkB.TK+ mice displayed increased latency to immobility in the forced swim test, suggesting resistance to behavioral despair. 5. Fluoxetine increased the latency to immobility in wild-type mice to a similar level as seen in the trkB.TK+ mice after saline treatment, but had no further behavioral effect in the swimming behavior of the trkB.TK+ mice. 6. Only minor differences in the levels of brain monoamines and their metabolites were observed between the transgenic and wild-type mice. 7. These data, together with other recent observations, suggest that trkB activation may play a critical role in the behavioral responses to antidepressant drugs in mice.

Interaction between BDNF and Serotonin: Role in Mood Disorders

“…Fluoxetine was able to increase the latency to immobility in wild-type mice to similar levels as the TrkB.TK + mice. Despite the differences in resistance to behavioral despair observed between the TrkB.TK + and the wild-type mice, only minor differences in levels of brain monoamines were observed (Koponen et al, 2005).…”

“…Further supporting the main role of BDNF as mediating an antidepressant response, enhanced BDNF signaling resulting from overexpression of the full-length TrkB receptor (trkB.TK + ), results in an antidepressant-like behavioral response (Koponen et al, 2005). TrkB.TK + mice display increased latency to immobility in the forced swim test, suggesting an increase in resistance to 'behavioral despair,' which is an excellent predictor of antidepressant efficacy.…”

Pharmacologically Diverse Antidepressants Rapidly Activate Brain-Derived Neurotrophic Factor Receptor TrkB and Induce Phospholipase-Cγ Signaling Pathways in Mouse Brain

“…injection of antidepressant or saline and tested in the FST (30 min following injection) (Porsolt et al, 1977;Koponen et al, 2005) or killed for biochemical assays (30, 60, or 120 min following drug administration). The following antidepressant drugs and doses were used: FLX-HCl (20-30 mg/kg, Sigma-Aldrich Finland Oy, Helsinki, Finland; OrionPharma Turku, Finland; or kindly provided by GlaxoSmithKline (GSK), Verona, Italy), citalopram-HBr (20 mg/kg, kindly provided by GSK), imipramine-HCl (30 mg/kg, Sigma-Aldrich), clomipramine-HCl (20 mg/kg, Sigma-Aldrich), reboxetine (free base) (20 mg/kg, kindly provided by GSK), and moclobemide (free base) (20 mg/kg, kindly provided by F Hoffmann-La Roche Ltd, Basel, Switzerland).…”

“…TrkB.TKÀ mice (n ¼ 35) and their WT littermates (n ¼ 44) were tested in the FST (Koponen et al, 2005) 30 min after the injection of citalopram (20 mg/kg), reboxetine (20 mg/ kg), or saline without a pre-swim. The behavioral parameter recorded was latency to immobility.…”

“…A growing body of evidence suggests that BDNF-mediated TrkB signaling is both sufficient and necessary for antidepressant-like behaviors in rodents. Infusion of BDNF or overexpression of TrkB receptors produces antidepressant-like behavioral responses in the preclinical models of behavioral despair (Siuciak et al, 1997;Shirayama et al, 2002;Koponen et al, 2005). We recently demonstrated that the behavioral effects of two antidepressants, imipramine and fluoxetine (FLX) were abolished in transgenic mice with reduced BDNF levels or inhibited TrkB signaling in brain (Saarelainen et al, 2003) and this observation was subsequently confirmed in forebrain-specific BDNF null mice by using desipramine (Monteggia et al, 2004(Monteggia et al, , 2007, which shows a relatively high affinity to norepinephrine transporter (NET) when compared with imipramine and FLX.…”