Mechanisms of ketamine action as an antidepressant

Abstract

Clinical studies have demonstrated that a single sub-anesthetic dose of the dissociative anesthetic ketamine induces rapid and sustained antidepressant actions. Although this finding has been met with enthusiasm, ketamine's widespread use is limited by its abuse potential and dissociative properties. Recent preclinical research has focused on unraveling the molecular mechanisms underlying the antidepressant actions of ketamine in an effort to develop novel pharmacotherapies, which will mimic ketamine's antidepressant actions but lack its undesirable effects. Here we review hypotheses for the mechanism of action of ketamine as an antidepressant, including synaptic or GluN2B-selective extra-synaptic N-methyl-D-aspartate receptor (NMDAR) inhibition, inhibition of NMDARs localized on GABAergic interneurons, inhibition of NMDAR-dependent burst firing of lateral habenula neurons, and the role of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor activation. We also discuss links between ketamine's antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor (BDNF), eukaryotic elongation factor 2 (eEF2), mechanistic target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3). Mechanisms that do not involve direct inhibition of the NMDAR, including a role for ketamine's (R)-ketamine enantiomer and hydroxynorketamine (HNK) metabolites, specifically (2R,6R)-HNK, are also discussed. Proposed mechanisms of ketamine's action are not mutually exclusive and may act in a complementary manner to exert acute changes in synaptic plasticity, leading to sustained strengthening of excitatory synapses, which are necessary for antidepressant behavioral actions. Understanding the molecular mechanisms underpinning ketamine's antidepressant actions will be invaluable for the identification of targets, which will drive the development of novel, effective, next-generation pharmacotherapies for the treatment of depression.

Conflict of interest statement

Conflicts of interest

P.Z. and T.D.G. are listed as co-authors in a patent applications related to the pharmacology and use of (2S,6S)- and (2R,6R)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation and post-traumatic stress disorders.

Figures

Figure 1. Proposed mechanisms of ketamine action as an antidepressant

(A) Disinhibition hypothesis: Based on the disinhibition hypothesis, ketamine is proposed to selectively block N-methyl-D-aspartate receptors (NMDARs) expressed on GABAergic inhibitory interneurons, which leads to a disinhibition of pyramidal neurons and enhanced glutamatergic firing. Evoked released glutamate binds to and activates post-synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) resulting in enhanced brain-derived neurotrophic factor (BDNF) release, activation of the tropomyosin receptor kinase B (TrkB) receptor and subsequently promotion of protein synthesis via the activation of the mechanistic target of rapamycin complex 1 (mTORC1). (B) Inhibition of extra-synaptic NMDARs: Ketamine is proposed to selectively block extra-synaptic GluN2B-containing NMDARs, which are tonically activated by low levels of ambient glutamate regulated by the glutamate transporter 1 located on astrocytes. Inhibition of the extra-synaptic GluN2B-NMDARs is hypothesized to de-suppress mTORC1 function, which in turn will induce protein synthesis. (C) Blockade of spontaneous NMDAR activation: This hypothesis proposes that ketamine blocks NMDAR-mediated spontaneous neurotransmission, which results in the inhibition of the eukaryotic elongation factor 2 kinase (eEF2K) activity, thus preventing phosphorylation of its eEF2 substrate. This effect subsequently leads to an enhancement of BDNF translation. (D) Ketamine hydroxynorketamine (HNK) metabolites: This hypothesis posits that ketamine exerts NMDAR inhibition-independent antidepressant actions via the action of its metabolites, (2R,6R)-HNK and (2S,6S)-HNK. Ketamine is metabolized to HNKs following administration, and these HNK metabolites act to promote AMPAR-mediated synaptic potentiation. These mechanisms of ketamine action are not mutually exclusive and may act complementary in exerting the antidepressant actions of the drug as all hypotheses propose acute changes in synaptic plasticity, leading to sustained strengthening of excitatory synapses, being necessary for antidepressant responses. Abbreviations: EAAT2, excitatory amino acid transporter 2; GABA, gamma aminobutyric acid; GSK, glycogen synthase kinase