title: Defining the role of corticotropin releasing factor binding protein in alcohol consumption.
abstract: The corticotropin releasing factor (CRF) exerts its effects by acting on its receptors and on the binding protein (CRFBP), and has been implicated in alcohol use disorder (AUD). Therefore, identification of the exact contribution of each protein that mediates CRF effects is necessary to design effective therapeutic strategies for AUD. A series of in vitro/in vivo experiments across different species were performed to define the biological discrete role of CRFBP in AUD. First, to establish the CRFBP role in receptor signaling, we developed a novel chimeric cell-based assay and showed that CFRBP full length can stably be expressed on the plasma membrane. We discovered that only CRFBP(10 kD) fragment is able to potentiate CRF-intracellular Ca2+release. We provide evidence that CRHBP gene loss increased ethanol consumption in mice. Then, we demonstrate that selective reduction of CRHBP expression in the center nucleus of the amygdala (CeA) decreases ethanol consumption in ethanol-dependent rats. CRFBP amygdalar downregulation, however, does not attenuate yohimbine-induced ethanol self-administration. This effect was associated with decreased hemodynamic brain activity in the CRFBP-downregulated CeA and increased hemodynamic activity in the caudate putamen during yohimbine administration. Finally, in alcohol-dependent patients, genetic variants related to the CRFBP(10 kD) fragment were associated with greater risk for alcoholism and anxiety, while other genetic variants were associated with reduced risk for anxiety. Taken together, our data provide evidence that CRFBP may possess both inhibitory and excitatory roles and may represent a novel pharmacological target for the treatment of AUD.
authors.affiliation: Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, NIAAA DICBR and NIDA IRP, NIH, Bethesda, MD, USA.|Center for Alcohol and Addiction Studies, Department of Psychiatry and Human Behavior, Brown University, Providence, RI, USA.|Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Haass-Koffler
authors.affiliation: Department of Psychology, University of Chicago, Chicago, IL, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Henry
authors.affiliation: Department of Radiology, University of Ottawa, Ottawa, ON, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Melkus
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Simms
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Naemmuddin
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: C K
authors.initials: CK
authors.lastname: Nielsen
authors.affiliation: Department of Psychiatry, University of Illinois, Chicago, IL, USA.
authors.forename: A W
authors.initials: AW
authors.lastname: Lasek
authors.affiliation: Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Magill
authors.affiliation: Office of the Clinical Director, NIAAA, NIH, Bethesda, MD, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Schwandt
authors.affiliation: Clinical Neuroimaging Research Core, NIAAA, NIH, Bethesda, MD, USA.
authors.forename: R
authors.initials: R
authors.lastname: Momenan
authors.affiliation: Laboratory of Neurogenetics, NIAAA, NIH, Rockville, MD, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Hodgkinson
authors.affiliation: Queensland University of Technology, Brisbane, QLD, Australia.
authors.forename: S E
authors.initials: SE
authors.lastname: Bartlett
authors.affiliation: Center for Alcohol and Addiction Studies, Department of Psychiatry and Human Behavior, Brown University, Providence, RI, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Swift
authors.affiliation: NIDA Intramural Research Program and Departments of Neuroscience and Psychiatry, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bonci
authors.affiliation: Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, NIAAA DICBR and NIDA IRP, NIH, Bethesda, MD, USA.|Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI, USA.
authors.forename: L
authors.initials: L
authors.lastname: Leggio
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics* / Q000503:physiopathology; D000437:Alcoholism / Q000235:genetics* / Q000503:physiopathology; D000679:Amygdala / Q000503:physiopathology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D002462:Cell Membrane / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D012039:Regional Blood Flow / Q000235:genetics; D013045:Species Specificity; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; C067133:corticotropin releasing factor-binding protein; D002118:Calcium