title: Nucleus incertus corticotrophin-releasing factor 1 receptor signalling regulates alcohol seeking in rats.
abstract: Alcoholism is a chronic relapsing disorder, and stress is a key precipitant of relapse. The nucleus incertus (NI) is highly responsive to corticotrophin-releasing factor (CRF) and psychological stressors, receives a CRF innervation and expresses CRF1and CRF2receptor mRNA. Furthermore, the ascending NI relaxin-3 system is implicated in alcohol seeking in rats. Therefore, in alcohol-preferring rats, we examined the effect of bilateral injections into the NI of the CRF1receptor antagonist, CP376395 or the CRF2receptor antagonist, astressin-2B on yohimbine-induced reinstatement of alcohol seeking. Using quantitative PCR analysis of NI micropunches, we assessed the effects of chronic alcohol consumption on gene expression profiles for components of the relaxin-3 and CRF systems. Bilateral intra-NI injections of CP376395 (500 ng/0.25 µl) attenuated yohimbine-induced reinstatement of alcohol seeking. In contrast, intra-NI injections of astressin-2B (200 ng/0.25 µl) had no significant effect. In line with these data, CRF1, but not CRF2, receptor mRNA was upregulated in the NI following chronic ethanol intake. Relaxin family peptide 3 receptor mRNA was also increased in the NI following chronic ethanol. Our quantitative PCR analysis also identified CRF mRNA within the rat NI, and the existence of a newly identified population of CRF-containing neurons was subsequently confirmed by detection of CRF immunoreactivity in rat and mouse NI. These data suggest that NI neurons contribute to reinstatement of alcohol seeking, via an involvement of CRF1signalling. Furthermore, chronic ethanol intake leads to neuroadaptive changes in CRF and relaxin-3 systems within rat NI.
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, 3052, Australia.|Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria, 3010, Australia.
authors.forename: Leigh C
authors.initials: LC
authors.lastname: Walker
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, 3052, Australia.|Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria, 3010, Australia.
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Kastman
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, 3052, Australia.|Institute for Interdisciplinary Studies, University of Amsterdam, Amsterdam, 1098 XH, the Netherlands.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Koeleman
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, 3052, Australia.|Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria, 3010, Australia.|School of Medicine, Deakin University, Geelong, Victoria, 3216, Australia.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Smith
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, 3052, Australia.|Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria, 3010, Australia.
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Perry
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, 3052, Australia.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Krstew
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, 3052, Australia.|Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria, 3010, Australia.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Gundlach
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, 3052, Australia.|Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria, 3010, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lawrence
mesh_terms: D000437:Alcoholism / Q000378:metabolism* / Q000503:physiopathology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D058999:Drug-Seeking Behavior / Q000502:physiology*; D008297:Male; D051379:Mice; D016133:Polymerase Chain Reaction; D011903:Raphe Nuclei / Q000378:metabolism*; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000099052:CRF Receptor, Type 1
chemical_list: D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1
keywords: alcohol; corticotrophin-releasing factor; nucleus incertus; reinstatement; relaxin-3; stress