title: Behavioral, biological, and chemical perspectives on targeting CRF(1) receptor antagonists to treat alcoholism.
abstract: BACKGROUND
  Alcohol use disorders are chronic disabling conditions for which existing pharmacotherapies have only modest efficacy. In the present review, derived from the 2012 Behavior, Biology and Chemistry "Translational Research in Addiction" symposium, we summarize the anti-relapse potential of corticotropin-releasing factor type 1 (CRF(1)) receptor antagonists to reduce negative emotional symptoms of acute and protracted alcohol withdrawal and stress-induced relapse to alcohol seeking.
  
  
  METHODS
  We review the biology of CRF(1) systems, the activity of CRF(1) receptor antagonists in animal models of anxiolytic and antidepressant activity, and experimental findings in alcohol addiction models. We also update the clinical trial status of CRF(1) receptor antagonists, including pexacerfont (BMS-562086), emicerfont (GW876008), verucerfont (GSK561679), CP316311, SSR125543A, R121919/NBI30775, R317573/19567470/CRA5626, and ONO-2333Ms. Finally, we discuss the potential heterogeneity and pharmacogenomics of CRF(1) receptor pharmacotherapy for alcohol dependence.
  
  
  RESULTS
  The evidence suggests that brain penetrant-CRF(1) receptor antagonists have therapeutic potential for alcohol dependence. Lead compounds with clinically desirable pharmacokinetic properties now exist, and longer receptor residence rates (i.e., slow dissociation) may predict greater CRF(1) receptor antagonist efficacy. Functional variants in genes that encode CRF system molecules, including polymorphisms in Crhr1 (rs110402, rs1876831, rs242938) and Crhbp genes (rs10055255, rs3811939) may promote alcohol seeking and consumption by altering basal or stress-induced CRF system activation.
  
  
  CONCLUSIONS
  Ongoing clinical trials with pexacerfont and verucerfont in moderately to highly severe dependent anxious alcoholics may yield insight as to the role of CRF(1) receptor antagonists in a personalized medicine approach to treat drug or alcohol dependence.
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA. ezorrilla@scripps.edu
authors.forename: Eric P
authors.initials: EP
authors.lastname: Zorrilla
authors.forename: Markus
authors.initials: M
authors.lastname: Heilig
authors.forename: Harriet
authors.initials: H
authors.lastname: de Wit
authors.forename: Yavin
authors.initials: Y
authors.lastname: Shaham
mesh_terms: D000437:Alcoholism / Q000188:drug therapy*; D000818:Animals; D001007:Anxiety / Q000139:chemically induced*; D002986:Clinical Trials as Topic; D003865:Major Depressive Disorder / Q000139:chemically induced*; D004195:Disease Models, Animal; D055808:Drug Discovery; D000431:Ethanol / Q000009:adverse effects*; D006801:Humans; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*
chemical_list: D018019:Receptors, Corticotropin-Releasing Hormone; D000431:Ethanol