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

Abstract

Rationale A number of preclinical and clinical studies suggest ketamine, a glutamate NMDA (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 AMPA (alpha-amino-3-hydroxy-5-methyl–4-isoxazolepropionic acid) 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 (WKY) rats, a putative animal model of depression. Results Chronic AMPA treatment resulted in a dose dependent antidepressant effect in both the forced swim test (FST) and sucrose preference test. Moreover, chronic administration (10–11d) 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 (BDNF), synapsin, and mammalian target of rapamycin (mTOR). 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.

Repeated ketamine treatment induces sex-specific behavioral and neurochemical effects in mice

“…The beneficial effects of repeated ketamine treatment observed in male mice are consistent with earlier studies that have investigated the antidepressant-like effects of various repeated ketamine treatment regimens in rodents [27][28][29][30][31][32]. Of note, the adverse effects of repeated ketamine treatment observed in females fit nicely with our recent finding that a single dose of ketamine (10 mg/kg) may induce rapid sex-specific anxiety-like effects in female mice subjected to the OFT [18].…”

“…The sub-anesthetic doses of ketamine implemented and route of administration selected are commonly used to screen for the antidepressant-like effects of ketamine in preclinical rodent models [18,26]. Earlier studies have implemented similar drug regimens to investigate the antidepressant-like effects of repeated ketamine treatment in rodents [27][28][29][30][31][32] (Table 1). In an initial dose-dependent study we wondered whether male and female mice would display differential responsiveness to increasing doses of repeated ketamine treatment in the open field test (OFT) and the FST (Fig.…”

Effects of single-dose ketamine infusion on behavioral parameters and neuronal activation in the medial prefrontal cortex of juvenile rats exposed to prenatal stress

“…In another study, administration of a low dose of ketamine (0.5 mg/kg) for 10 days significantly increased sucrose consumption in Wistar-Kyoto rats. [35] Furthermore, Li et al [22] reported that even a single-dose of ketamine produces a long lasting (up to 7 days) increase in sucrose preference relative to chronic unpredictable stress exposed animals. Protracted effects of acute ketamine treatment were also evident in mice exposed to chronic mild stress that is tested at 4, 6, and 8 days after a single ketamine treatment.…”

Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism

“…Preclinically, AMPARpositive allosteric modula tors (or AMPAkines, such as LY392098, LY451646 and Org 26576), 6,28,50,51 the AMPAR agonist CX546 20 and AMPA itself 52 have dosedependent antidepressant activity in rodents and can enhance the effects of ketamine when coadministered as an adjunctive. In addition, the AMPAkine Org 26576 showed some (although not significant) efficacy, good tolerability and even cognitive enhancement in depressed patients in a small pilot phase 1b clinical trial, but further investigation of AMPAkines for depression is needed.…”

“…20,29 Moreover, administra tion of AMPAkines appears to mimic these key molecular effects of ketamine and can be abolished by NBQX. 6,20,30,33,34,48,51,52 Accumulating evidence indicates that ketamine enhances synaptogenesis and connectivity in the hippocampus, prefrontal cortex and associated regions via the activation of key signalling pathways, including those involving BDNF and mTOR. 5 At the level of neural circuits, both animal and human imaging studies suggest that by acti vating these signalling cascades, ketamine is able to effect ively reverse the loss of connectivity between the PFC and other limbic structures (e.g., amygdala) in depressed individ uals.…”