title: Acute oral administration of the novel, competitive and selective glucocorticoid receptor antagonist ORG 34517 reduces the severity of ethanol withdrawal and related hypothalamic-pituitary-adrenal axis activation.
abstract: BACKGROUND
  The development of ethanol dependence is associated with alterations in hypothalamic-pituitary-adrenal (HPA) axis and activation of type II glucocorticoid receptors (GR). These effects may contribute to withdrawal-associated anxiety, craving and relapse to drinking. The present studies examined acute and oral administration of the novel, selective and competitive GR antagonist ORG 34517 on the severity of ethanol withdrawal.
  
  
  METHODS
  Adult, male Sprague-Dawley rats were administered ethanol (4g/kg/i.g.) twice daily for 5 days followed by 2 days of withdrawal for 1, 2 or 3 consecutive cycles. Blood ethanol levels (BELs) were determined at 0930 on Day 4 of each week, while blood corticosterone levels (BCLs) were obtained at 11:00hours on the first day of each ethanol withdrawal. During early withdrawal, subjects received oral administration of ORG 345617 (60mg/kg/i.g.) or a placebo and withdrawal was monitored.
  
  
  RESULTS
  Peak BELs of 225.52mg/dl were observed during the third week. Withdrawal from three cycles of the regimen produced marked behavioral abnormalities (e.g., aggression, rigidity, and hypoactivity) and significant increases in BCLs of ethanol-dependent subjects. Acute, oral administration of ORG 34517 during early withdrawal significantly reduced both the severity of ethanol withdrawal, as reflected in reduced rigidity, aggression, and hypoactivity, and elevations in BCL without producing any sedative-like effects.
  
  
  CONCLUSIONS
  The present findings demonstrate that repeated ethanol exposure and withdrawal is associated with significant behavioral abnormalities and dysregulation of HPA axis activation. Further these data suggest that selective GR antagonists should be further considered as putative pharmacotherapies for treatment of ethanol dependence.
authors.affiliation: University of Kentucky, Department of Psychology, United States; University of Kentucky, Spinal Cord and Brain Injury Research Center, United States.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Reynolds
authors.affiliation: University of Kentucky, Department of Psychology, United States; University of Kentucky, Spinal Cord and Brain Injury Research Center, United States.
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Saunders
authors.affiliation: University of Kentucky, Department of Psychology, United States; University of Kentucky, Spinal Cord and Brain Injury Research Center, United States.
authors.forename: Honoree' W
authors.initials: HW
authors.lastname: Brewton
authors.affiliation: University of Kentucky, Department of Psychology, United States; University of Kentucky, Spinal Cord and Brain Injury Research Center, United States.
authors.forename: Sydney R
authors.initials: SR
authors.lastname: Winchester
authors.affiliation: University of Kentucky, Department of Psychology, United States; University of Kentucky, Spinal Cord and Brain Injury Research Center, United States.
authors.forename: Ibrahim S
authors.initials: IS
authors.lastname: Elgumati
authors.affiliation: University of Kentucky, Department of Psychology, United States; University of Kentucky, Spinal Cord and Brain Injury Research Center, United States. Electronic address: prender@uky.edu.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Prendergast
mesh_terms: D000284:Administration, Oral; D000428:Alcohol Drinking / Q000097:blood / Q000523:psychology; D000437:Alcoholism / Q000097:blood / Q000523:psychology; D000818:Animals; D052117:Benzodioxoles / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D003345:Corticosterone / Q000097:blood; D000431:Ethanol / Q000009:adverse effects* / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000378:metabolism; D011605:Psychoses, Substance-Induced / Q000097:blood / Q000188:drug therapy / Q000523:psychology; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D013256:Steroids / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D013375:Substance Withdrawal Syndrome / Q000097:blood / Q000188:drug therapy* / Q000523:psychology
chemical_list: D052117:Benzodioxoles; C526064:Org 34517; D011965:Receptors, Glucocorticoid; D013256:Steroids; D000431:Ethanol; D003345:Corticosterone
keywords: Dependence; Ethanol; Glucocorticoid; Hypothalamic–pituitary–adrenal-axis; Withdrawal