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. 2022 Apr 15;2(1):9. doi: 10.1007/s44192-022-00012-3

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© The Author(s) 2022

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — Proposed mechanisms of action of ketamine and esketamine. Ketamine’s (and esketamine’s) actions at the glutamate receptor that may mediate antidepressant effects include: (1) blocking the N-methyl-D-aspartate (NMDA) receptor at the gamma aminobutyric acid (GABA)-ergic inhibitory interneuron, leading to disinhibition of presynaptic neurons and resulting in increased glutamate release into the synapse (disinhibition hypothesis). Other downstream molecular and cellular pathways have also been investigated to better understand ketamine’s rapid acting antidepressant properties and its effects on promoting neuroplasticity. These include: (2) inhibition of synaptic and (3) extra-synaptic NMDA receptors leading to intracellular pathways promoting neuroplasticity; (4) inhibitory effects of the NMDA receptor in the lateral habenula (LHb) neurons; (5) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation from increased synaptic glutamate release and/or ketamine metabolites (e.g., (2R, 6R)-hydroxynorketamine (HNK)); and (6) presynaptic metabotropic glutamate receptor (mGluR) (group II) antagonism leading to enhanced glutamate release and subsequent AMPA receptor activation, leading to downstream molecular and cellular pathways promoting neuroplasticity. Adapted with permission from [21].