Unlike d-fenfluramine, which has a selective dual action on serotonin by blocking reuptake and stimulating release, the antidepressant imipramine inhibits monoamine reuptake to enhance serotonergic and noradrenergic activity in the brain. Interestingly, chronic, but not acute imipramine treatment significantly increased phosphorylation of FoxO1 and FoxO3a, as well as moderately increased phosphorylation of Akt. Additional to modulating monoamine neurotransmission, chronic antidepressant treatment, including imipramine, is known to increase brain BDNF (67, 68), a neurotrophin that also phosphorylates and inactivates FoxOs (48, 56). Thus, imipramine may have increased FoxO phosphorylation by enhancing serotonin action and increasing brain BDNF. Since the therapeutic effect of an antidepressant typically requires prolonged treatment, the observation from this study links FoxO1 and FoxO3a to a clinically relevant treatment for anxiety and depression. We examined this role of FoxOs by taking advantage of mice with genetically modified FoxO1 and FoxO3a.
