Antidepressant‐like effect of AMPA and ketamine combination in male Wistar ‐Kyoto rats

A combination of the drugs AMPA and ketamine produced a stronger antidepressant effect in male Wistar-Kyoto rats than either drug alone. Rats received AMPA (0.25 mg/kg) and ketamine (0.25 mg/kg) together for 10 days, and their behavior was tested with a forced swim test about 22 hours after the last injection. The combination significantly reduced immobility, a measure of helplessness, compared to individual treatments. The finding suggests that increasing AMPA/NMDA receptor function may mediate ketamine's antidepressant effects and that combining AMPA with ketamine could be an effective treatment for depression.

Study at a glance

Abstract

Studies have shown that therapeutics that act on the glutamatergic system could provide a novel mechanistic approach for the treatment of depression. We previously reported that ketamine, an NMDA antagonist, has a rapid and lasting antidepressant effect both acutely and chronically on depressive‐like behavior in Wistar‐Kyoto (WKY) rats ( Soc Neurosci Abst 2008) . Other studies had suggested that the antidepressant effect elicited by ketamine could be mediated through stimulation of AMPA receptors, we also sought to confirm this hypothesis in our animal model of depression. We discovered that AMPA by itself also has an antidepressant effects in WKY rats, both acutely and chronically ( Biol Psych Abst 2010). In this study we examined the hypothesis that the combination of AMPA and ketamine will result in either a synergistic or additive antidepressant effect when compared to the individual treatments of AMPA or ketamine alone. Adult male WKY rats were administered the combination of AMPA (0.25 mg/kg, i.p.) and ketamine (0.25 mg/kg, i.p.) for 10 days and behavior studies were done approximately 22 hr after the last injection. Controls received saline. A 5 minute forced swim test (FST), a measure of helplessness, was used to determine the drug‐induced antidepressant effects. The combination of AMPA and ketamine resulted in a significant reduction of FST immobility compared to individual treatment of either AMPA or ketamine alone. In view of the fact that an increase in AMPA/NMDA receptor function and number may be mediating the antidepressant effects of ketamine, these results suggest that a combination of AMPA and ketamine could provide an effective therapeutic treatment for depression. Supported by NIH/NIGMS (2 SO6 GM08016‐39)