title: Chronic Unpredictable Mild Stress Induces Loss of GABA Inhibition in Corticotrophin-Releasing Hormone-Expressing Neurons through NKCC1 Upregulation.
abstract: BACKGROUND
  Prolonged and repeated stresses cause hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. The corticotrophin-releasing hormone (CRH)-expressing neurons in the hypothalamic paraventricular nucleus (PVN) are an essential component of the HPA axis.
  
  
  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.
  
  
  CONCLUSIONS
  These data suggest that chronic stress impairs GABAergic inhibition, resulting in HPA axis hyperactivity through upregulation of NKCC1.
authors.affiliation: Department of Anesthesiology & Perioperative Medicine, The University of Texas MD Anderson Cancer Center.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Anesthesiology & Perioperative Medicine, The University of Texas MD Anderson Cancer Center.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Zhou
authors.affiliation: Department of Anesthesiology & Perioperative Medicine, The University of Texas MD Anderson Cancer Center.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Psychology, the University of Houston.
authors.forename: Therese
authors.initials: T
authors.lastname: Kosten
authors.affiliation: Department of Critical Care, The University of Texas MD Anderson Cancer Center.
authors.forename: De-Pei
authors.initials: DP
authors.lastname: Li
mesh_terms: D000818:Animals; D002034:Bumetanide / Q000008:administration & dosage; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D058785:GABA-A Receptor Agonists / Q000008:administration & dosage; D058787:GABA-A Receptor Antagonists / Q000008:administration & dosage; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009118:Muscimol / Q000008:administration & dosage; D009433:Neural Inhibition; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D011724:Pyridazines / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000008:administration & dosage; D064506:Solute Carrier Family 12, Member 2 / Q000378:metabolism*; D013315:Stress, Psychological / Q000378:metabolism / Q000503:physiopathology*; D015854:Up-Regulation; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D011724:Pyridazines; D011963:Receptors, GABA-A; C578879:Slc12a2 protein, rat; D049994:Sodium Potassium Chloride Symporter Inhibitors; D064506:Solute Carrier Family 12, Member 2; D002034:Bumetanide; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D003346:Corticotropin-Releasing Hormone; C049853:gabazine; D003345:Corticosterone