Although models such as the FST and TST are widely used as tests of antidepressant efficacy, additional appreciation of the potential value of AMPAR potentiation in animal models of depression should be gained. However, only one study has previously evaluated this mechanism in antidepressant-detecting assays that require subchronic dosing (Knapp et al. Additional preclinical support comes from the finding that AMPAR subunit 1 (GluR-A) knockout mice show increased learned helplessness (Chourbaji et al. 2008) as effective antidepressants for treatment-resistant depression, identification of AMPAR potentiation as a potential mechanism for these effects (Maeng et al. 2006) and NR2B receptor blockade (CP101,606) (Preskorn et al. Given the clinical validation of ketamine (Zarate et al. NBQX also prevented antidepressant-like effects of the NMDA receptor antagonists ketamine, MK801 and Ro25-6981, an NR2B antagonist (Maeng et al. NBQX also prevented both antidepressant-like effects in the TST and serotonin increases in the medial prefrontal cortex induced by MGS0039 an mGluR 2/3 receptor antagonist with antidepressant potential (Karasawa et al. 2008) and GYKI 53655, another AMPA antagonist, prevented the effects of LY392098 in the FST and TST (Li et al. Thus, the AMPA antagonists NBQX and GYKI 52466 reduced the effects of lithium in the FST and/or TST (Gould et al. Data from studies using AMPA antagonists have further implicated a role for AMPAR activation in mediating antidepressant-like actions of a number of either clinically used or experimental compounds. AMPAR potentiators result in neurobiological adaptations similar to those produced by antidepressants that are currently used in the clinical setting, including BDNF induction and increases in hippocampal progenitor cell proliferation (reviewed in Alt et al. There is also an increasing body of proof-of-concept evidence suggesting a role for AMPARs in depression and in the actions of antidepressant drugs.

Specifically, AMPAR potentiators such as LY392098 are active in both the forced swim test (FST) and the tail suspension test (TST), two behavioural despair models that are used to screen and identify compounds with antidepressant activity (Bai et al. Our results demonstrate that, in the UCMS paradigm, AMPAR activation exhibits antidepressant-like activity that relates preferentially to specific depressive-like responses and that those specific responses can be defined by their regulation by AMPAR modulation under conditions of stress.ĪMPA potentiator, chronic mild stress, glutamate, mood disorders, plasticity IntroductionĪMPA receptor (AMPAR) activation is currently considered as one of the most promising new approaches for new antidepressant therapies as the balance between glutamate and GABA in general is becoming increasingly relevant in the field of depression.ĭirect evidence comes from preclinical models of antidepressant activity. Thus, the antidepressant-like effects of LY392098 were fully predicted by the AMPAR dependence of effects demonstrated for fluoxetine. In the same protocol, the AMPAR antagonist GYKI (10 mg/kg) reversed most, but not all, of the antidepressant-like actions of fluoxetine. However, LY392098 did not restore sucrose preference and did not reduce anxiety (marble-burying) in stressed mice. The AMPAR potentiator LY392098 (5 mg/kg), when administered alone, functioned like classic antidepressants by reducing weight loss, fur deterioration and immobility in the tail suspension test. After 3 wk of UCMS, BALB/c mice developed a number of depressive-like behaviours that were successfully prevented by fluoxetine (20 mg/kg) administration. We investigated the role of AMPARs in antidepressant action in an unpredictable chronic mild stress (UCMS) model in BALB/c mice. Nevertheless, studies on AMPAR function in chronic animal models used to predict antidepressant efficacy are surprisingly lacking. Enhancement of AMPA receptor (AMPAR) function has emerged as a novel strategy for treatment of depression.

Beam breaks actimeter