State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Institute of Clinical Pharmacology & Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
J Pharm Pharmacol. 2023 Apr 17;75(5):686-692. doi: 10.1093/jpp/rgad016.
Fluoxetine has been used as the first line for the therapy of depression. However, lack of therapeutic efficacy and time lag still limit the application of fluoxetine. Gap junction dysfunction is a potentially novel pathogenic mechanism for depression. To clarify the mechanism underlying these limitations, we investigated whether gap junction was related to the antidepressant effects of fluoxetine.
After chronic unpredictable stress (CUS), animals showed decreases in gap junction intracellular communication (GJIC). Treatment with fluoxetine 10 mg/kg significantly improved GJIC and anhedonia of rats until six days. These results indicated that fluoxetine improved gap junction indirectly. Furthermore, to test the role of gap junction on antidepressant effects of fluoxetine, we blocked gap junction using carbenoxolone (CBX) infusion in the prefrontal cortex. CBX dampened fluoxetine-induced decrease in immobility time of mice in tail suspension test (TST).
Our study suggested that gap junction dysfunction blocks antidepressant effects of fluoxetine, contributing to understanding the mechanism underlying the time lag of fluoxetine.
氟西汀已被用作治疗抑郁症的一线药物。然而，缺乏治疗效果和时滞仍然限制了氟西汀的应用。缝隙连接功能障碍是抑郁症潜在的新发病机制。为了阐明这些限制的机制，我们研究了缝隙连接是否与氟西汀的抗抑郁作用有关。
在慢性不可预知的应激（CUS）后，动物的缝隙连接细胞内通讯（GJIC）减少。氟西汀 10mg/kg 治疗可显著改善大鼠的 GJIC 和快感缺失，直至 6 天。这些结果表明氟西汀间接改善了缝隙连接。此外，为了测试缝隙连接对氟西汀抗抑郁作用的作用，我们使用前脑皮质中的 carbenoxolone（CBX）输注来阻断缝隙连接。CBX 抑制了氟西汀诱导的悬尾试验（TST）中小鼠不动时间的减少。
我们的研究表明，缝隙连接功能障碍阻断了氟西汀的抗抑郁作用，有助于理解氟西汀时滞的机制。
