The role of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in depression: Central mediators of pathophysiology and antidepressant activity?

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

“…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.…”

“…42 Interestingly, postmortem studies have re ported reductions in the mRNA expression levels of AMPA receptor subunits GluA1 and GluA3 in the perirhinal cortex, CA1 and dentate gyrus 44 of patients with depression, and several animal studies similarly found that exposure to chronic stress leads to a decrease in the expression of AMPAR subunits in these brain regions. [44][45][46] Sitespecific AMPAR phosphorylation at serine, threonine or tyrosine resi dues in the intracellular Cterminal domain by various protein kinases is known to modulate the channel kinetics, localization, subunit composition and protein-protein inter actions of AMPARs. 28 In addition to regulating the number of AMPA receptors on the surface, ketamine has been shown to affect the phosphorylation state of AMPAR subunits.…”

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

“…94 Ketamine was shown to increase BDNF in the hippocampus but this effect was not sustained after 24 h. 20 Our results do not allow us to determine if ketamine alters the levels of BDNF in the NAc and VTA, because the levels of this growth factor were unaltered 24 h after the injection, which might indicate that BDNF levels have already returned to baseline levels both in the NAc and VTA. Enhanced AMPAR function, as demonstrated by, for example, enhanced AMPA/NMDA ratio, increased glutamatergic synaptic transmission or increased phosphorylation of GluA1, 5,7,38,86,95 was suggested to mediate synaptic plasticity underlying the antidepressant effects of ketamine and (2R,6R)-HNK. These observations were made in the hippocampus or prefrontal cortex.…”

“…6 These data, along with data on the antidepressant effects of AMPAkines, implicate AMPARs as potent pharmacological targets for the development of effective treatment of depression. 7 However, it should be noted that a recent study could not demonstrate antidepressant action of (2R,6R)-HNK in two mouse models of depression although ketamine was potent in alleviating depression-like symptoms in these models. 8 Further research on the ability of ketamine and its metabolites to modulate AMPARs as a mechanism of rapid and lasting antidepressant actions is warranted.…”

Duality of Antidepressants and Neuroprotectants

“…Indeed, it has been shown that AMPA itself can exert an antidepressant effect in an animal model of depression (Akinfiresoye and Tizabi 2013). Moreover, clinical studies indicate that expression of AMPA receptors is altered in patients with depression (Freudenberg et al 2015). Thus, future studies on AMPA receptor subtype involvement in depression may offer novel pharmacological interventions.…”