Abstract
Previous studies suggest that brain-derived neurotrophic factor and its receptor TrkB are critically involved in the therapeutic actions of antidepressant drugs. We have previously shown that the antidepressants imipramine and fluoxetine produce a rapid autophosphorylation of TrkB in the rodent brain. In the present study, we have further examined the biochemical and functional characteristics of antidepressant-induced TrkB activation in vivo. We show that all the antidepressants examined, including inhibitors of monoamine transporters and metabolism, activate TrkB rapidly in the rodent anterior cingulate cortex and hippocampus. Furthermore, the results indicate that acute and long-term antidepressant treatments induce TrkB-mediated activation of phospholipase-Cγ1 (PLCγ1) and increase the phosphorylation of cAMP-related element binding protein, a major transcription factor mediating neuronal plasticity. In contrast, we have not observed any modulation of the phosphorylation of TrkB Shc binding site, phosphorylation of mitogen-activated protein kinase or AKT by antidepressants. We also show that in the forced swim test, the behavioral effects of specific serotonergic antidepressant citalopram, but not those of the specific noradrenergic antidepressant reboxetine, are crucially dependent on TrkB signaling. Finally, brain monoamines seem to be critical mediators of antidepressant-induced TrkB activation, as antidepressants reboxetine and citalopram do not produce TrkB activation in the brains of serotonin- or norepinephrine-depleted mice. In conclusion, our data suggest that rapid activation of the TrkB neurotrophin receptor and PLCγ1 signaling is a common mechanism for all antidepressant drugs.
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Acknowledgements
We thank L Kaskela, O Nikkilä, M-E Hokkanen, J Knuuttila, and M Sairanen for excellent technical assistance; S Pastell and V Nousiainen for the animal care and OF O'Leary for critical reading of this paper and for her help in planning the pCPA administration. Fluoxetine for long-term treatments was kindly provided by Dr J Sirviö (OrionPharma, Turku, Finland). Moclobemide was obtained from Roche. This study was supported by grants from the Sigrid Juselius Foundation, the Academy of Finland, GlaxoSmithKline, the Research and Science Foundation of Farmos and the Finnish Cultural Foundation.
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Rantamäki, T., Hendolin, P., Kankaanpää, A. et al. Pharmacologically Diverse Antidepressants Rapidly Activate Brain-Derived Neurotrophic Factor Receptor TrkB and Induce Phospholipase-Cγ Signaling Pathways in Mouse Brain. Neuropsychopharmacol 32, 2152–2162 (2007). https://doi.org/10.1038/sj.npp.1301345
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DOI: https://doi.org/10.1038/sj.npp.1301345
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