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Introduction: Prolonged and repeated stresses cause hyperactivity of the hypothalamic-pituitaryadrenal(HPA)axis.The corticotrophin-releasing hormone(CRH)-expressing neurons in the hypothalamic paraventricular nucleus(PVN)are an essential component of the HPA axis.Materials and Methods: Chronic unpredictable mild stress(CUMS)was induced in Sprague-Dawley rats.GABA reversal potentials(EGABA)were determined by using gramicidin-perforated recordings in identified PVN-CRH neurons through expressing enhanced green fluorescent protein driven by the CRH promoter.Plasma corticosterone(CORT)levels were measured in rats implanted with a cannula targeting the lateral ventricles and PVN.Results: Blocking the GABAA receptor in the PVN with gabazine significantly increased plasma CORT levels in unstressed rats but did not change CORT levels in CUMS rats.CUMS caused a depolarizing shift in EGABA in PVN CRH neurons compared with EGABA in PVN-CRH neurons in unstressed rats.Furthermore,CUMS induced a long-lasting increase in expression levels of the cation chloride cotransporter Na+-K+-Cl–-Cl–(NKCC1)in the PVN but a transient decrease in expression levels of K+-Cl–-Cl– in the PVN,which returned to the basal level 5 days after CUMS treatment.The NKCC1 inhibitor bumetanide decreased the basal firing activity of PVN-CRH neurons and normalized EGABA and the gabazine-induced excitatory effect on PVN-CRH neurons in CUMS rats.In addition,central administration of bumetanide decreased basal circulating CORT levels in CUMS rats.