Antidepressant effects of AMPA and ketamine combination: role of hippocampal BDNF, synapsin, and mTOR

A number of preclinical and clinical studies suggest that ketamine, a glutamate N-methyl-d-aspartate receptor antagonist, has a rapid and lasting antidepressant effect when administered either acutely or chronically. It has been postulated that this effect is due to stimulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In this study, we tested whether AMPA alone has an antidepressant effect and if the combination of AMPA and ketamine provides added benefit in Wistar-Kyoto rats, a putative animal model of depression. Chronic AMPA treatment resulted in a dose-dependent antidepressant effect in both the forced swim test and sucrose preference test. Moreover, chronic administration (10-11 days) of combinations of AMPA and ketamine, at doses that were ineffective on their own, resulted in a significant antidepressant effect. The behavioral effects were associated with increases in hippocampal brain-derived neurotrophic factor, synapsin, and mammalian target of rapamycin. These findings are the first to provide evidence for an antidepressant effect of AMPA and suggest the usefulness of AMPA-ketamine combination in treatment of depression. Furthermore, these effects appear to be associated with increases in markers of hippocampal neurogenesis and synaptogenesis, suggesting a mechanism of their action.