title: Brain-specific inactivation of the Crhr1 gene inhibits post-dependent and stress-induced alcohol intake, but does not affect relapse-like drinking.
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.
authors: Institute of Psychopharmacology, Central Institute of Mental Health (CIMH), University of Heidelberg, Mannheim, Germany.
authors: Anna
authors: A
authors: Molander
authors: Valentina
authors: V
authors: Vengeliene
authors: Markus
authors: M
authors: Heilig
authors: Wolfgang
authors: W
authors: Wurst
authors: Jan M
authors: JM
authors: Deussing
authors: Rainer
authors: R
authors: Spanagel
mesh_terms: D020268:Alcohol-Induced Disorders, Nervous System / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000437:Alcoholism / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D020868:Gene Silencing; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013315:Stress, Psychological / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D000099052:CRF Receptor, Type 1
chemical_list: D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1