Delta opioid receptor agonists activate PI3K-mTORC1 signaling in parvalbumin-positive interneurons in mouse infralimbic prefrontal cortex to exert acute antidepressant-like effects

Delta opioid receptor (DOP) agonists can produce acute antidepressant-like effects, with a specific intracellular mechanism involving the PI3K-Akt-mTORC1 pathway. In mouse behavioral models, the selective DOP agonist KNT-127 reduced immobility in the forced swimming test and improved depression-related phenotypes in a chronic vicarious social defeat stress paradigm, including social avoidance and sucrose consumption. These antidepressant-like responses were blocked by inhibitors of PI3K and mTOR. Cell and circuit mechanisms point to infralimbic prefrontal cortex (IL-PFC) regulation of excitation and inhibition: KNT-127 increased phosphorylation of mTOR pathway proteins (Akt and p70S6 kinase), altered synaptic currents in IL-PFC slices, and showed DOP expression largely in parvalbumin-positive interneurons. The findings suggest DOP agonists suppress GABA release from these interneurons to enhance pyramidal neuron excitation via PI3K-Akt-mTORC1-p70S6 kinase signaling.