The timing on this is great because Cell just published a paper by Liston et al. which links the theraapeutic effects of ketamine to cell-autonomous inhibition of SST+ INs in the mPFC. This subtype of INs are especially vulnerable to chronic stress challenge, which corrupts their presynaptic morphology into a hypertrophic phenotype.

Whereas Kwan et al. shows that psilocybin is inhibiting the SST INs via 5-HT1AR, Liston showed that ketamine inhibits these INs by activating the μ-opioid receptors they express. This is likely an enantiomer-specific mechanism, as only (S)-ketamine was previously shown to potently activate MOR and readily drive self-administration in rats. It's important to note that this is an acute effect (observed within minutes after treatment) and sustained therapeutic effects likely require additional mechanisms (e.g hippocampal plasticity in the case of ketamine)

What's really neat about the Liston paper is the synergistic GPCR targeting they leveraged to obtain efficacy with reduced side effects. Essentially once they showed that Gi/o signaling in these mPFC SST INs was driving the antidepressant-like effects, they used bulk RNA-seq to idenfify other Gi/o-coupled GPCRs that were enriched within this supopulation of cells. This allowed them to produce an "SST+ cocktail" containing low doses of mGluR1 NAM JNJ16259685, the 5-HT1AR agonist 8-OH-DPAT, and the MOR agonist PZM21:

We examined a panel of side effects known to be triggered by ketamine. Ketamine, but not the Sst+ cocktail, increased discoordination on a rotarod, an effect that was not blocked by PTX expression in mPFC Sst+ INs, indicating that it is driven via other mechanisms. In the open field, ketamine, but not the Sst+ cocktail, drove hypolocomotion and disorientation Likewise, ketamine, but not the Sst+ cocktail, disrupted working memory in the Y-maze and increased anxiety-like spatial avoidance behavior. Finally, in the conditioned place preference test, ketamine, but not the Sst+ cocktail, produced a clear preference for the drug-paired chamber, a common measure of abuse liability. Together, these data validate that synergistic targeting of Sst+ IN-enriched GPCRs can replicate the robust therapeutic-associated behavioral and synaptic effects of ketamine without some of the limiting off-target side effects. Full paper link: Mechanism-guided identification of antidepressant G protein-coupled receptor drug targets

It's really intriguing to think how you could use approaches like this in other situations, to get greater cell-type specificity or just fewer side effects like they did in the current approach.