Jennifer A Rinker1, S Alex Marshall1, Christopher M Mazzone2, Emily G Lowery-Gionta2, Varun Gulati3, Kristen E Pleil4, Thomas L Kash2, Montserrat Navarro1, Todd E Thiele5. 1. Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 2. Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Pharmacology, University of North Carolina at Chapel Hill, , Chapel Hill, North Carolina. 3. Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 4. Department of Pharmacology, University of North Carolina at Chapel Hill, , Chapel Hill, North Carolina. 5. Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Electronic address: thiele@unc.edu.
Abstract
BACKGROUND: Corticotropin-releasing factor (CRF) signaling at the CRF1 receptor (CRF1R) in the ventral tegmental area (VTA) can modulate ethanol consumption in rodents. However, the effects of binge-like ethanol drinking on this system have not been thoroughly characterized, and little is known about the role of CRF2R or the CRF neurocircuitry involved. METHODS: The effects of binge-like ethanol consumption on the VTA CRF system were assessed following drinking-in-the-dark procedures. Intra-VTA infusions of selective CRF1R and/or CRF2R compounds were employed to assess the contributions of these receptors in modulating binge-like ethanol consumption (n = 89). To determine the potential role of CRF projections from the bed nucleus of the stria terminalis (BNST) to the VTA, CRF neurons in this circuit were chemogenetically inhibited (n = 32). Binge-induced changes in VTA CRF system protein and messenger RNA were also assessed (n = 58). RESULTS: Intra-VTA antagonism of CRF1R and activation of CRF2R resulted in decreased ethanol intake, which was eliminated by simultaneous blockade of both receptors. Chemogenetic inhibition of local CRF neurons in the VTA did not alter binge-like ethanol drinking, but inhibition of VTA-projecting CRF neurons from the BNST significantly reduced intake. CONCLUSIONS: We provide novel evidence that 1) blunted binge-like ethanol consumption stemming from CRF1R blockade requires intact CRF2R signaling, and CRF2R activation reduces binge-like drinking; 2) inhibiting VTA-projecting BNST CRF neurons attenuates binge-like drinking; and 3) binge-like ethanol drinking alters protein and messenger RNA associated with the VTA-CRF system. These data suggest that ethanol-induced activation of BNST-to-VTA CRF projections is critical in driving binge-like ethanol intake.
BACKGROUND:Corticotropin-releasing factor (CRF) signaling at the CRF1 receptor (CRF1R) in the ventral tegmental area (VTA) can modulate ethanol consumption in rodents. However, the effects of binge-like ethanol drinking on this system have not been thoroughly characterized, and little is known about the role of CRF2R or the CRF neurocircuitry involved. METHODS: The effects of binge-like ethanol consumption on the VTA CRF system were assessed following drinking-in-the-dark procedures. Intra-VTA infusions of selective CRF1R and/or CRF2R compounds were employed to assess the contributions of these receptors in modulating binge-like ethanol consumption (n = 89). To determine the potential role of CRF projections from the bed nucleus of the stria terminalis (BNST) to the VTA, CRF neurons in this circuit were chemogenetically inhibited (n = 32). Binge-induced changes in VTA CRF system protein and messenger RNA were also assessed (n = 58). RESULTS: Intra-VTA antagonism of CRF1R and activation of CRF2R resulted in decreased ethanol intake, which was eliminated by simultaneous blockade of both receptors. Chemogenetic inhibition of local CRF neurons in the VTA did not alter binge-like ethanol drinking, but inhibition of VTA-projecting CRF neurons from the BNST significantly reduced intake. CONCLUSIONS: We provide novel evidence that 1) blunted binge-like ethanol consumption stemming from CRF1R blockade requires intact CRF2R signaling, and CRF2R activation reduces binge-like drinking; 2) inhibiting VTA-projecting BNST CRF neurons attenuates binge-like drinking; and 3) binge-like ethanol drinking alters protein and messenger RNA associated with the VTA-CRF system. These data suggest that ethanol-induced activation of BNST-to-VTA CRF projections is critical in driving binge-like ethanol intake.
Authors: Blaine N Armbruster; Xiang Li; Mark H Pausch; Stefan Herlitze; Bryan L Roth Journal: Proc Natl Acad Sci U S A Date: 2007-03-02 Impact factor: 11.205
Authors: Emily G Lowery-Gionta; Montserrat Navarro; Chia Li; Kristen E Pleil; Jennifer A Rinker; Benjamin R Cox; Gretchen M Sprow; Thomas L Kash; Todd E Thiele Journal: J Neurosci Date: 2012-03-07 Impact factor: 6.167
Authors: Marisa Roberto; Maureen T Cruz; Nicholas W Gilpin; Valentina Sabino; Paul Schweitzer; Michal Bajo; Pietro Cottone; Samuel G Madamba; David G Stouffer; Eric P Zorrilla; George F Koob; George R Siggins; Loren H Parsons Journal: Biol Psychiatry Date: 2010-01-08 Impact factor: 13.382
Authors: Samuel W Centanni; Bridget D Morris; Joseph R Luchsinger; Gaurav Bedse; Tracy L Fetterly; Sachin Patel; Danny G Winder Journal: Neuropsychopharmacology Date: 2018-11-02 Impact factor: 7.853
Authors: Rafael E Perez; Aakash Basu; Bretton P Nabit; Nicholas A Harris; Oakleigh M Folkes; Sachin Patel; Ralf Gilsbach; Lutz Hein; Danny G Winder Journal: Neuropsychopharmacology Date: 2020-02-19 Impact factor: 7.853
Authors: Rianne R Campbell; Racquel D Domingo; Amy R Williams; Melissa G Wroten; Hadley A McGregor; Ryan S Waltermire; Daniel I Greentree; Scott P Goulding; Andrew B Thompson; Kaziya M Lee; Sema G Quadir; C Leonardo Jimenez Chavez; Michal A Coelho; Adam T Gould; Georg von Jonquieres; Matthias Klugmann; Paul F Worley; Tod E Kippin; Karen K Szumlinski Journal: J Neurosci Date: 2019-02-08 Impact factor: 6.167