Antidepressant drugs for beta amyloid-induced depression: A new standpoint?

Mounting evidence suggests that depression represents a risk factor and an early manifestation of Alzheimer's disease (AD). Neuropsychiatric symptoms may derive from neurobiological changes in specific brain areas and may be considered prodromal of dementia. We have previously reported the depressive-like profile in rats receiving a single intracerebroventricular injection of soluble amyloid beta protein (beta A). Here, we verified the effect of different classes of antidepressants on the beta A-induced depressive behavior and on cortical monoamine levels. To these purposes, the forced swimming test was performed and cortical levels of serotonin (5-HT) and noradrenaline (NA) were quantified by high performance liquid chromatography (HPLC). We found that acute fluoxetine (20 mg/kg, s.c.), reboxetine (10 mg/kg, s.c.), and ketamine (15 mg/kg, i.p.) significantly reduced the immobility in beta A-treated rats compared to controls. Fluoxetine and reboxetine reversed 5-HT reduction, while DA-induced NA increase was further enhanced by all treatments. Treatments with fluoxetine, reboxetine and ketamine were able to revert soluble beta A-induced decrease of cortical BDNF levels, while only fluoxetine and ketamiiie, but not reboxetine, had the same effects on cortical NGF expression. Moreover, plasma soluble beta A-levels were lowered by fluoxetine, but not reboxetine and ketamine, treatments. Our data suggest that different classes of antidepressants yield a short-acting effect on rat soluble beta A-induced depressive profile. Thus, we hypothesize a novel common mechanism of action of these drugs also based upon a beta A lowering effect. Although further investigations are still needed, our study might open a new scenario for unravelling the molecular antidepressant mechanisms of these drugs.