Brain-specific inactivation of the Crhr1 gene inhibits post-dependent and stress-induced alcohol intake, but does not affect relapse-like drinking

Anna Molander, Valentina Vengeliene, Markus Heilig, Wolfgang Wurst, Jan M. Deussing, Rainer Spanagel

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

Corticotropin-releasing hormone (CRH) and its receptor, CRH receptor-1 (CRHR1), have a key role in alcoholism. Especially, post-dependent and stress-induced alcohol intake involve CRH/CRHR1 signaling within extra-hypothalamic structures, but a contribution of the hypothalamic-pituitary- adrenal (HPA) axis activity might be involved as well. Here we examined the role of CRHR1 in various drinking conditions in relation to HPA and extra-HPA sites, and studied relapse-like drinking behavior in the alcohol deprivation model (ADE). To dissect CRH/CRHR1 extra-HPA and HPA signaling on a molecular level, a conditional brain-specific Crhr1-knockout (Crhr1 NestinCre) and a global knockout mouse line were studied for basal alcohol drinking, stress-induced alcohol consumption, deprivation-induced intake, and escalated alcohol consumption in the post-dependent state. In a second set of experiments, we tested CRHR1 antagonists in the ADE model. Stress-induced augmentation of alcohol intake was lower in Crhr1 NestinCre mice as compared with control animals. Crhr1 NestinCre mice were also resistant to escalation of alcohol intake in the post-dependent state. Contrarily, global Crhr1 knockouts showed enhanced stress-induced alcohol consumption and a more pronounced escalation of intake in the post-dependent state than their control littermates. Basal intake and deprivation-induced intake were unaltered in both knockout models when compared with their respective controls. In line with these findings, CRHR1 antagonists did not affect relapse-like drinking after a deprivation period in rats. We conclude that CRH/CRHR1 extra-HPA and HPA signaling may have opposing effects on stress-related alcohol consumption. CRHR1 does not have a role in basal alcohol intake or relapse-like drinking situations with a low stress load.

Original languageEnglish
Pages (from-to)1047-1056
Number of pages10
JournalNeuropsychopharmacology
Volume37
Issue number4
DOIs
StatePublished - Mar 2012

Keywords

  • alcohol deprivation effect (ADE)
  • alcoholism
  • conditional Crhr1NestinCre-knockout mice
  • post-dependent drinking
  • relapse
  • stress

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