In the last years it has been proposed that the antidepressant action is mediated not only by changes in monoamine levels but
also in association with modifications involving cell proliferation and plasticity in some brain limbic areas as hippocampus, and also
frontal cortex and amygdala. This leads to the merging of the classic “monoaminergic hypothesis of depression”, with the newer “neurotrophic
hypothesis of depression”. Here we review two important signaling pathways: the Wnt/β-catenin pathway —implicated in cellular
proliferation and synaptic plasticity— that is downregulated in major depression and upregulated after antidepressant treatment; and
the mTOR pathway —controling synaptic plasticity— recently related to present disrupted functioning in major depression, and as the
target of some drugs with fast-acting potential antidepressant action. These pieces of evidences are confirmed in a variety of animal models
of depression and are predictive of antidepressant actions. We also review the role of another two important neurotrophic factors:
brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) that mediate the antidepressant effects. All of
the above intracellular pathways interact by a crosstalk mediated by Akt, a key regulator molecule that may underlie the fine tuning between
proliferative and neuroplasticity changes induced by antidepressant drugs.
Keywords: β-catenin, GSK-3β, mTOR, BDNF, synaptic plasticity, neurogenesis, antidepressant drugs.
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