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 (Crhr1NestinCre) 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 Crhr1NestinCre mice as compared with control animals. Crhr1NestinCre 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.
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Acknowledgements
We thank Sabrina Koch for technical assistance. This work was supported by the Bundesministerium für Bildung und Forschung (NGFN Plus; FKZ: 01GS08152, FKZ: 01GS08155 see under www.ngfn-alkohol.de and Spanagel et al, 2010; FKZ: 01GS08151) and Svenska Sällskapet för Medicinsk Forskning (SSMF).
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All authors report having no conflict of interest, financial or otherwise. The authors declare that over the past 3 years RS has received compensations for research and consultant contracts from Abbott, GSK, Solvay, and Xenoport.
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Molander, A., Vengeliene, V., Heilig, M. et al. Brain-Specific Inactivation of the Crhr1 Gene Inhibits Post-Dependent and Stress-Induced Alcohol Intake, but Does Not Affect Relapse-Like Drinking. Neuropsychopharmacol 37, 1047–1056 (2012). https://doi.org/10.1038/npp.2011.297
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DOI: https://doi.org/10.1038/npp.2011.297
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