15th Oct 2020
In their recent article, “(2S,6S)- and (2R,6R)- hydroxynorketamine inhibit the induction of NMDA receptor-dependent LTP at hippocampal CA1 synapses in mice”, in the British Neuroscience Association (BNA) journal, Brain and Neuroscience Advances, Kang et al. (2020) report that two metabolites of ketamine are able to impair NMDA receptor-dependent LTP.
It has been known since the pioneering experiments of BNA member David Lodge FRS, published in 1983, that ketamine 
is an NMDA receptor antagonist. In the same year, another BNA member and former President, Graham Collingridge FRS, showed that NMDA receptors are critical for the induction of a form of synaptic plasticity known as long-term potentiation (LTP).
In more recent times, ketamine has been shown to display rapid and persistent antidepressant actions that last from days to weeks, and (S)-ketamine has received FDA approval for the treatment of depression. Lodge, Collingridge, and their teams have speculated that ketamine has this remarkable antidepressant action by modulating synaptic plasticity within mood pathways in the brain.
In their recent publication, Kang et al. (2020) report that two metabolites of ketamine are able to impair NMDA receptor-dependent LTP. The (2R,6R)-hydroxynorketamine (HNK) metabolite, in particular, has been shown previously to have rapid antidepressant effects in rodents.
However, its mechanism of action was initially proposed to be independent of NMDA receptors – a view that has since been challenged.
This new study by Kang et al. now demonstrates that, like ketamine, these HNK metabolites interfere with NMDA receptor-dependent LTP. The simplest explanation for these findings is that HNK inhibits LTP by antagonising NMDA receptors, though other mechanisms cannot be excluded.
Precisely how ketamine and its HNK metabolites work as rapid antidepressants is unknown and remains an important topic for future investigation. However, it could be that they act by blocking NMDA receptor-dependent retrieval and/or reconsolidation of unpleasant memories, therefore helping to break the ongoing cycle of a negative mood state.
In other words, in the presence of these drugs, one may simply forget about one’s depression.
Click here to read the full article
Brain and Neuroscience Advances is a peer-reviewed, open-access journal, which publishes high quality translational and clinical articles from all neuroscience disciplines; including molecular, cellular, systems, behavioural and cognitive investigations.
The journal welcomes submissions in basic, translational and/or clinical neuroscience. Research papers should present novel, empirical results that are expected to be of interest to a broad spectrum of neuroscientists working in the laboratory, field or clinic.
Brain and Neuroscience Advances is now indexed in PubMed Central.
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