The strain-dependent antidepressant-like activity of Yueju Pill: An electrophysiological, and behavioral pharmacological study

The antidepressant efficacy exhibits significant individual variation influenced by genetic factors. Traditional Chinese Medicine (TCM) as a personalized medicine, is intrinsically linked to genetic variation, but experimental investigation remains scarce. This study investigated the genetic impacts of the antidepressant effects of Yueju Pill (YJ), a classic TCM formula, using Balb/c and C57BL/6 J mouse strains, and underlying electrophysiological and molecular mechanisms. We found that the same dose of YJ induced immediate and sustained antidepressant-like effects exclusively in Balb/c mice, accompanied by a specific enhancement of long-term potentiation (LTP) in the hippocampus. These effects were absent in C57BL/6 J mice. Further pharmacological validation confirmed the key role of the PKA-CREB pathway: treatment with the PKA signaling inhibitor H-89, administered either before or after YJ, completely blocked its antidepressant effects, indicating that this pathway is essential for both the initiation and maintenance of its efficacy. Notably, a comparative analysis with ketamine revealed mechanistic differences between the two: PKA activation was not required for the initiation of ketamine's antidepressant effect, and its role in the early maintenance stage was only observed when PKA was inhibited prior to ketamine administration. Furthermore, in the LPS-induced inflammatory depression model using Balb/c mice, YJ also demonstrated antidepressant effects 24 hours after a single administration. Western blot analysis of hippocampal tissue revealed that YJ treatment significantly down‑regulated the protein expression of phospho‑NF‑κB (p‑NF‑κB) and the microglial marker Iba1, indicating a suppression of neuroinflammatory activation. In summary, differences in genetic background may influence the behavioral and electrophysiological effects of YJ. The activation of PKA signaling is required for both the initiation and early maintenance of its antidepressant actions, and attenuation of neuroinflammation, as evidenced by reduced p‑NF‑κB and Iba1 expression, may also contribute to its effects.