Fast-acting antidepressant-like effects of ketamine in aged male rats.

A single dose of ketamine produced a fast-acting antidepressant-like effect in 14-month-old male rats, reducing immobility in the forced-swim test within 30 minutes, accompanied by increased levels of mature brain-derived neurotrophic factor (mBDNF) in the prefrontal cortex. However, repeated daily ketamine for 7 days did not sustain antidepressant-like effects and instead decreased mBDNF in the same brain region. Neither acute nor repeated ketamine altered hippocampal cell proliferation or other neurotrophic markers. The findings extend evidence for ketamine's rapid antidepressant potential to older age, but the loss of efficacy with repeated dosing and possible adverse effects in aging require further investigation.

Study at a glance

Abstract

The aging process causes anatomical and physiological changes that predispose to the development of late-life depression while reduces the efficacy of classical antidepressants. Novel fast-acting antidepressants such as ketamine might be good candidates to be explored in the context of aging, especially given the lack of previous research on its efficacy for this age period. Thus, the aim of the present study was to characterize ketamine's effects in older rats. The fast-acting (30 min) and repeated (7 days) antidepressant-like effects of ketamine (5 mg/kg, ip) were evaluated in 14-month-old single-housed rats through the forced-swim and novelty-suppressed feeding tests. In parallel, the modulation of neurotrophic-related proteins (i.e., mBDNF, mTOR, GSK3) was assessed in brain regions affected by the aging process, prefrontal cortex and hippocampus, as well as possible changes in hippocampal cell proliferation. Acute ketamine induced a fast-acting antidepressant-like response in male aged rats, as observed by a reduced immobility in the forced-swim test, in parallel with a region-specific increase in mBDNF protein content in prefrontal cortex. However, repeated ketamine failed to induce antidepressant-like efficacy, but decreased mBDNF protein content in prefrontal cortex. The rate of hippocampal cell proliferation and/or other markers evaluated was not modulated by either paradigm of ketamine. These results complement prior data supporting a fast-acting antidepressant-like effect of ketamine in rats, to further extend its efficacy to older ages. Future studies are needed to further clarify the lack of response after the repeated treatment as well as its potential adverse effects in aging.