This work attempts to discuss whether dexmedetomidine (Dex) can protect rats from postoperative cognitive dysfunction (POCD) through regulating the γ‐aminobutyric acid‐B receptor (GABABR)‐mediated cyclic adenosine monophosphate (cAMP) – protein kinase A (PKA) – cAMP‐response element binding (cAMP‐PKA‐CREB) signaling pathway. Sprague‐Dawley rats were divided into a non‐surgical group (Control), a surgical group (Model), a surgical group treated with Dex (Model + Dex), a surgical group treated with GABABR antagonist (Model + CGP 35348) and a surgical group treated with Dex and GABABR agonist (Model + Dex + Baclofen). Cognitive and memory functions were evaluated by Y‐maze test and open‐field test. The neuronal morphology of the hippocampus was observed by hematoxylin and eosin staining and neuronal apoptosis was by terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin nick‐end labeling method. Inflammatory factors and cAMP levels were detected by enzyme‐linked immunosorbent assay while expressions of GABABR and PKA‐CREB pathway‐related molecules by Western blot. Compared with control rats, the model rats exhibited reduced alternation rates with a prolonged time spent in the central zone; meanwhile, levels of tumor necrosis factor‐α and interleukin‐1β and the apoptotic index, as well as GABABR1 and GABABR2 expressions were increased in the model rats, but the cAMP‐PKA‐CREB pathway was inhibited (all P < 0.05). When treated with either Dex or CGP 35348, the surgical rats displayed an opposite tendency concerning the above factors as compared to the model rats (all P < 0.05). Furthermore, Baclofen, the agonist of GABABR, could reverse the protective effect of Dex against POCD in rats. Dex protects rats from POCD possibly via suppressing GABABR to up‐regulate the cAMP‐PKA‐CREB signaling pathway, thereby alleviating the hippocampal inflammation caused by surgical trauma.

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