%0 Journal Article
%T The Ketamine Metabolite 2R,6R-Hydroxynorketamine Blocks NMDA Receptors and Impacts Downstream Signaling Linked to Antidepressant Effects
%A Ege T Kavalali
%A Lisa M Monteggia
%J Archive of "Neuropsychopharmacology".
%D 2018
%R 10.1038/npp.2017.210
%X Clinical studies have demonstrated a reproducible rapid antidepressant effect of low-dose ketamine in patients with depressive symptoms. However, ketamine¡¯s dissociative side effects and abuse potential has led to the search for identification of alternative compounds that trigger rapid antidepressant effects without the psychotomimetic side effects. A successful effort will require elucidation of the molecular mechanisms that elicit the antidepressant effects of ketamine. In 2011, our group proposed a synaptic signaling pathway that can account for ketamine¡¯s antidepressant-like effects in preclinical animal models (Autry et al, 2011). Specifically, we showed that ketamine-mediated block of resting synaptic NMDA receptor (NMDAR) activity¡ªdriven by spontaneous glutamate release¡ªleads to deactivation of eEF2 kinase resulting in dephosphorylation of its sole known target eEF2. The dephosphorylation of eEF2 results in desuppresion of dendritic protein translation and a rapid subsequent increase in brain-derived neurotrophic factor (BDNF) expression. Released BDNF activates TrkB receptors and triggers a subsequent potentiation of AMPA receptor (AMPAR)-mediated synaptic transmission in the hippocampus, providing a synaptic basis for the antidepressant effects of ketamine (Autry et al, 2011; Nosyreva et al, 2013). Consistent with the premise, ketamine¡¯s antidepressant effects have previously been shown to require AMPARs as NBQX, an AMPAR antagonist, attenuates the antidepressant effects in rodents (Maeng et al, 2008; Autry et al, 2011). Importantly, the model we proposed can account for the ineffectiveness of the NMDAR blocker memantine as an antidepressant in the clinic, as memantine¡ªunlike ketamine¡ªhas a limited ability to block resting NMDAR function. However, a recent study challenged a key component of the model by suggesting that ketamine¡¯s antidepressant action is mediated by its metabolite 2R,6R-hydroxynorketamine (2R,6R-HNK), via the same signaling pathway and AMPAR-mediated synaptic potentiation as outline above (Autry et al, 2011) but in a NMDAR-independent manner (Zanos et al, 2016). Validation of the same signaling pathway and effects on AMPAR-mediated potentiation¡ªsans NMDAR block¡ªprompted us to investigate the impact of 2R,6R-HNK on NMDAR-mediated neurotransmission. In recent experiments, we showed that 2R,6R-HNK can swiftly inhibit NMDAR transmission up to 50% at concentrations needed to trigger the intracellular signaling pathway involved in the potentiation of synaptic AMPAR responses, strongly supporting a role for NMDAR-blockade in this
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719113/