I can finally tweet about this epic tome by @brikchen with @alain_gardier, @DenisJDavid, @im74ve, @cgamma4, et al. In her most recent paper (her 2nd paper in 7 mo), we sought to determine if the metabolites of ketamine could act as prophylactics against stress. (1/11)

In our previous study, we showed that (R,S)-ketamine could protect against learned fear and behavioral despair in the FST in male mice. Interestingly, here, we found (2R,6R)-HNK and (2S,6S)-HNK protect against distinct stress-induced behaviors in male mice. (2/11)

(2S,6S)-HNK decreased learned fear, while (2R,6R)-HNK decreased immobility time in the FST. Most notably, we found that the metabolites were effective as prophylactics in incredibly small doses (e.g., 0.075 mg/kg for (2R,6R)-HNK). (3/11)

We previously showed that ketamine alters AMPAR-mediated synaptic transmission in CA3. Here, we report that (2R,6R)-HNK (like ketamine), but not (2S,6S)-HNK reduces large AMPA bursts, and that these actions are correlated with the drugs’ distinct behavioral effects. (4/11)

We next sought to determine whether (R,S)-ketamine or its metabolites could be prophylactic in female mice. In contrast to the males, none of the compounds attenuated fear. (5/11)

However, (R,S)-ketamine and (2R,6R)-HNK, but not (2S,6S)-HNK, were prophylactic against behavioral despair in the FST. We validated these effects with 2 other stress models – learned helplessness and chronic immobilization stress. (6/11)

Now earlier I mentioned the metabolite dosing in male. Interestingly, here in females, (R,S)-ketamine and (2R,6R)-HNK were effective at 1/3 of the dose given to males. These data would suggest that it is not a one size fits all for the sexes. (7/11)

We then hypothesized that increased drug sensitivity in female mice was dependent on ovarian-derived hormones. We performed ovariectomy (OVX) surgery on female mice only to find that (R,S)-ketamine and (2R,6R)-HNK were not effective as prophylactics anymore in OVX mice. (8/11)

We first tried giving estrogen (E2) to restore prophylactic efficacy – (2R,6R)-HNK was effective again. However, when we administered E2 and cyclic progesterone (P4) then (R,S)-ketamine was effective once more. (9/11)

Before I end this thread, some other interesting findings. 1) We do not get robust antidepressant effects of (R,S)-ketamine in all mouse strains (with or without stress). This should be considered in studies moving forward. (10/11)

There is more to discuss but we hope you enjoyed this thread and I’m super, super proud of @brikchen for getting this out there. Link to the paper: https://www.nature.com/articles/s41386-020-0714-z (11/11)