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

Abstract

Rationale: 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.

Objective: 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.

Results: 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.

Conclusion: 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.

Fig 1

Effects of various doses of AMPA on (a) FST immobility, (b) FST swimming, (c) sucrose preference, and (d) locomotor activity in WKY rats. Animals were treated once daily for 11 consecutive days. Values are mean ± SEM, *p<0.05 **p<0.01 compared to SAL, n=7–8.

Fig 1

Effects of various doses of AMPA on (a) FST immobility, (b) FST swimming, (c) sucrose preference, and (d) locomotor activity in WKY rats. Animals were treated once daily for 11 consecutive days. Values are mean ± SEM, *p<0.05 **p<0.01 compared to SAL, n=7–8.

Fig 1

Effects of various doses of AMPA on (a) FST immobility, (b) FST swimming, (c) sucrose preference, and (d) locomotor activity in WKY rats. Animals were treated once daily for 11 consecutive days. Values are mean ± SEM, *p<0.05 **p<0.01 compared to SAL, n=7–8.

Fig 2

Effect of low doses of AMPA (0.25 mg/kg or 0.5 mg/kg), ketamine (0.25 mg/kg or 0.5 mg/kg), and their combination on (a) FST immobility, (b) FST swimming, (c) sucrose preference, and (d) locomotor activity in WKY rats. Animals were treated once daily for 11 consecutive days. Values are mean ± SEM, *p<0.05 **p<0.01 compared to SAL, n=7–8

Fig 2

Effect of low doses of AMPA (0.25 mg/kg or 0.5 mg/kg), ketamine (0.25 mg/kg or 0.5 mg/kg), and their combination on (a) FST immobility, (b) FST swimming, (c) sucrose preference, and (d) locomotor activity in WKY rats. Animals were treated once daily for 11 consecutive days. Values are mean ± SEM, *p<0.05 **p<0.01 compared to SAL, n=7–8

Fig 2

Effect of low doses of AMPA (0.25 mg/kg or 0.5 mg/kg), ketamine (0.25 mg/kg or 0.5 mg/kg), and their combination on (a) FST immobility, (b) FST swimming, (c) sucrose preference, and (d) locomotor activity in WKY rats. Animals were treated once daily for 11 consecutive days. Values are mean ± SEM, *p<0.05 **p<0.01 compared to SAL, n=7–8

Fig 3

Effect of very low doses of AMPA (0.25 mg/kg), ketamine (0.25 mg/kg), and their combination on markers of neurogenesis (BDNF), synaptogenesis (synapsin) and the signal transduction protein (mTOR) in the hippocampus. (a) Immunoblots, (b) BDNF, (c) synapsin, (d) mTOR. Values are mean ± SEM, **p<0.01 compared to SAL, n=7–8.

Fig 3

Effect of very low doses of AMPA (0.25 mg/kg), ketamine (0.25 mg/kg), and their combination on markers of neurogenesis (BDNF), synaptogenesis (synapsin) and the signal transduction protein (mTOR) in the hippocampus. (a) Immunoblots, (b) BDNF, (c) synapsin, (d) mTOR. Values are mean ± SEM, **p<0.01 compared to SAL, n=7–8.

Fig 3

Effect of very low doses of AMPA (0.25 mg/kg), ketamine (0.25 mg/kg), and their combination on markers of neurogenesis (BDNF), synaptogenesis (synapsin) and the signal transduction protein (mTOR) in the hippocampus. (a) Immunoblots, (b) BDNF, (c) synapsin, (d) mTOR. Values are mean ± SEM, **p<0.01 compared to SAL, n=7–8.

Fig 4

Effect of low doses of AMPA (0.5 mg/kg), ketamine (0.5 mg/kg), and their combination on markers of neurogenesis (BDNF), synaptogenesis (synapsin), and the signal transduction protein (mTOR) in the hippocampus. (a) Immunoblots, (b) BDNF, (c) synapsin, (d) mTOR. Values are mean ± SEM, *p<0.05 **p<0.01 compared to SAL, n=7–8.

Fig 4

Effect of low doses of AMPA (0.5 mg/kg), ketamine (0.5 mg/kg), and their combination on markers of neurogenesis (BDNF), synaptogenesis (synapsin), and the signal transduction protein (mTOR) in the hippocampus. (a) Immunoblots, (b) BDNF, (c) synapsin, (d) mTOR. Values are mean ± SEM, *p<0.05 **p<0.01 compared to SAL, n=7–8.

Fig 4

Effect of low doses of AMPA (0.5 mg/kg), ketamine (0.5 mg/kg), and their combination on markers of neurogenesis (BDNF), synaptogenesis (synapsin), and the signal transduction protein (mTOR) in the hippocampus. (a) Immunoblots, (b) BDNF, (c) synapsin, (d) mTOR. Values are mean ± SEM, *p<0.05 **p<0.01 compared to SAL, n=7–8.