ON or OFF?: Modulating the N-Methyl-D-Aspartate Receptor in Major Depression

Abstract

Since the discovery that a single dose of ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, had rapid and long-lasting antidepressant effects, there has been increased interest in using NMDAR modulators in the pharmacotherapy of depression. Ketamine’s efficacy seems to imply that depression is a disorder of NMDAR hyperfunctionality. However, studies showing that not all NMDAR antagonists are able to act as antidepressants challenge this notion. Furthermore, NMDAR co-agonists have also been gaining attention as possible treatments. Co-agonists such as D-serine and sarcosine have shown efficacy in both pre-clinical models and human trials. This raises the question of how both NMDAR antagonists and agonists are able to have converging behavioral effects. Here we critically review the evidence and proposed therapeutic mechanisms for both NMDAR antagonists and agonists, and collate several theories on how both activation and inhibition of NMDARs appear to have antidepressant effects.

A pivot from synaptic monoamine processes to further downstream processes: The impact of ketamine research

“…15 Of note to remember: inhibiting receptor activation equals activating protein synthesis, which, as mentioned earlier, effects downstream signal transduction, likely involving increased dendritic spine density. 8,14,15 Introduction of an NMDA receptor co-agonist, then, such as Dserine, would encourage D-serine's occupation on otherwise inactivated NMDA-receptor glycine sites, a stimulating event, which would, it is postulated, result in long-term potentiation (LTP), the strengthening of synapses and signal transmission between neurons via recent activity-a synaptic plasticity phenome 16 and antidepressant effects. 15 So then, in this model, both NMDA-receptor antagonists and agonists potentiate signaling pathways, thereby increasing protein synthesis and AMPA-receptor activation, which in turn increase LTP initiation and facilitate synaptic plasticity.…”

“…15 They suggest that both the indirect and direct hypotheses can be true because seemingly opposite NMDA-receptor actions are location dependent. 15 In this theory, an NMDR antagonist, such as ketamine, would inhibit the constitutive stimulation of extra-synaptic NMDA receptors, resulting in activation of a signaling complex and protein synthesis. 15 Of note to remember: inhibiting receptor activation equals activating protein synthesis, which, as mentioned earlier, effects downstream signal transduction, likely involving increased dendritic spine density.…”

“…15 In this theory, an NMDR antagonist, such as ketamine, would inhibit the constitutive stimulation of extra-synaptic NMDA receptors, resulting in activation of a signaling complex and protein synthesis. 15 Of note to remember: inhibiting receptor activation equals activating protein synthesis, which, as mentioned earlier, effects downstream signal transduction, likely involving increased dendritic spine density. 8,14,15 Introduction of an NMDA receptor co-agonist, then, such as Dserine, would encourage D-serine's occupation on otherwise inactivated NMDA-receptor glycine sites, a stimulating event, which would, it is postulated, result in long-term potentiation (LTP), the strengthening of synapses and signal transmission between neurons via recent activity-a synaptic plasticity phenome 16 and antidepressant effects.…”

“…8,14,15 Introduction of an NMDA receptor co-agonist, then, such as Dserine, would encourage D-serine's occupation on otherwise inactivated NMDA-receptor glycine sites, a stimulating event, which would, it is postulated, result in long-term potentiation (LTP), the strengthening of synapses and signal transmission between neurons via recent activity-a synaptic plasticity phenome 16 and antidepressant effects. 15 So then, in this model, both NMDA-receptor antagonists and agonists potentiate signaling pathways, thereby increasing protein synthesis and AMPA-receptor activation, which in turn increase LTP initiation and facilitate synaptic plasticity. 15 In this way, NMDAreceptor antagonists and co-agonists have complementary actions which cause similar downstream antidepressant effects.…”

“…15 So then, in this model, both NMDA-receptor antagonists and agonists potentiate signaling pathways, thereby increasing protein synthesis and AMPA-receptor activation, which in turn increase LTP initiation and facilitate synaptic plasticity. 15 In this way, NMDAreceptor antagonists and co-agonists have complementary actions which cause similar downstream antidepressant effects. 15 Brain-derived neurotrophic factor (BDNF) studies have also contributed to these downstream signal transduction cascade theories.…”