Pharmacologically diverse antidepressants rapidly activate brain-derived neurotrophic factor receptor TrkB and induce phospholipase-Cgamma signaling pathways in mouse brain.
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-Cgamma1 (PLCgamma1) 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 PLCgamma1 signaling is a common mechanism for all antidepressant drugs.
Rantamäki
Tomi
T
Neuroscience Center, University of Helsinki, PO box 56, 00014 Helsinki, Finland.
Hendolin
Panu
P
Kankaanpää
Aino
A
Mijatovic
Jelena
J
Piepponen
Petteri
P
Domenici
Enrico
E
Chao
Moses V
MV
Männistö
Pekka T
PT
Castrén
Eero
E
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D015283:Citalopram / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006179:Gyrus Cinguli / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology; D051966:Phospholipase C gamma / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000077593:Reboxetine; D020813:Receptor, trkB / Q000819:agonists* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D015283:Citalopram; D017362:Cyclic AMP Response Element-Binding Protein; D009025:Morpholines; D051966:Phospholipase C gamma; D000077593:Reboxetine; D020813:Receptor, trkB; D017367:Selective Serotonin Reuptake Inhibitors