AMPA receptor stimulation mediates the antidepressant-like effect of a group II metabotropic glutamate receptor antagonist

Metabotropic Glutamate Receptors: Potential Drug Targets for Psychiatric Disorders

“…Interestingly, some of the actions of MGS0039 were attenuated by an AMPA receptor antagonist, NBQX [83,84], suggesting that MGS0039 exerts its effects through AMPA receptor activation. Given that AMPA receptor potentiators have been shown to exhibit antidepressant effects in animal models [85], and that AMPA receptor activation has been suggested to be involved in the antidepressant actions of ketamine and riluzole [86,87], which are effective antidepressant treatments, this mechanism is of interest in terms of the efficacy of mGlu2/3 receptor antagonists for the treating depression in the clinic.…”

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

“…22,33 Interestingly, preclinical studies indicate that group II metabotropic glutamate (mGlu2/3) receptor antagonists, such as MGS0039 and LY341495, possess ketaminelike anti depressant effects, which can also be blocked by NBQX pretreatment and thus similarly involve AMPAR stimu lation. 33,48 In addition, the SSRI fluoxetine and the TCA imipramine also are associated with upregulation of AMPARs in the hippocampus or mPFC, whereas their antidepressant action in the FST can be abolished by NBQX, indicating that facilitation of AMPARmediated signalling might represent a downstream point of convergence in the antidepressant action of ketamine and classical anti depressants. 45,49 Taken together, these data indicate that activation of AMPA receptors, both at the time of injection and at later time points, is required for both the rapid and sustained antidepressant actions of ketamine.…”

“…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.…”

Innovative approaches for the development of antidepressant drugs: Current and future strategies

“…MGS0039 and LY341495 are new, potent, and selective group II mGluR antagonists that exhibit antidepressant-like effects in rodent models of depression such as the forced swim and tail suspension tests. 103 Moreover, microdialysis studies demonstrated that MGS0039 can elevate serotonin levels in the mPFC, 104 and that both MGS0039 and LY341495 can increase the firing rate of serotonin neurons within the dorsal raphe nucleus. 105 These observations suggest that mGluR2/3 antagonists elicit antidepressant-like effects in part by facilitating serotonergic neurotransmission.…”