Jeffrey J Olney1,2, Montserrat Navarro1,2, Todd E Thiele1,2. 1. Department of Psychology & Neuroscience, University of North Carolina, Chapel Hill, North Carolina. 2. Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina.
Abstract
BACKGROUND: Recent reports have demonstrated that binge-like ethanol (EtOH) drinking leads to an increase in hypothalamic orexin (OX) signaling and that suppressing this signaling via systemic administration of an orexin receptor (OXR) antagonist blocks this behavior; however, the specific OX pathways that modulate this behavior remain unknown. The goal of this study was to further elucidate the role of the OX system in binge-like EtOH drinking using behavioral, molecular, and pharmacological techniques. METHODS: The drinking-in-the-dark (DID) paradigm was used to model binge-like drinking behavior in male C57BL/6J mice. Experiment 1 examined changes in the OX precursor, prepro-orexin, within the hypothalamus following multiple cycle EtOH or sucrose DID using polymerase chain reaction (PCR) analysis. In experiments 2a and 2b, we used site-directed infusion of an OXR antagonist to examine the individual contribution of each OXR subtype within the ventral tegmental area (VTA) and central nucleus of the amygdala (CeA), respectively, in binge-like EtOH or sucrose drinking. RESULTS: Findings from our PCR study revealed that multiple cycles of binge-like EtOH drinking did not lead to changes in prepro-orexin mRNA as a function of binge-like EtOH drinking. However, data from site-directed pharmacology studies indicate that the orexin-1 receptor (OX1R) is the predominate receptor subtype within the VTA and CeA that regulates binge-like EtOH drinking. Interestingly, inhibition of OX1Rs did not affect binge-like sucrose intake, which suggests that these OX circuits are specific for EtOH consumption. CONCLUSIONS: As a whole, these data suggest that the VTA and CeA are important regions in which OX regulates binge-like EtOH drinking behavior. Moreover, these findings identify OXR antagonists as a potential treatment option that may be used to ameliorate problematic drinking behavior while leaving responding to natural rewards relatively intact.
BACKGROUND: Recent reports have demonstrated that binge-like ethanol (EtOH) drinking leads to an increase in hypothalamic orexin (OX) signaling and that suppressing this signaling via systemic administration of an orexin receptor (OXR) antagonist blocks this behavior; however, the specific OX pathways that modulate this behavior remain unknown. The goal of this study was to further elucidate the role of the OX system in binge-like EtOH drinking using behavioral, molecular, and pharmacological techniques. METHODS: The drinking-in-the-dark (DID) paradigm was used to model binge-like drinking behavior in male C57BL/6J mice. Experiment 1 examined changes in the OX precursor, prepro-orexin, within the hypothalamus following multiple cycle EtOH or sucrose DID using polymerase chain reaction (PCR) analysis. In experiments 2a and 2b, we used site-directed infusion of an OXR antagonist to examine the individual contribution of each OXR subtype within the ventral tegmental area (VTA) and central nucleus of the amygdala (CeA), respectively, in binge-like EtOH or sucrose drinking. RESULTS: Findings from our PCR study revealed that multiple cycles of binge-like EtOH drinking did not lead to changes in prepro-orexin mRNA as a function of binge-like EtOH drinking. However, data from site-directed pharmacology studies indicate that the orexin-1 receptor (OX1R) is the predominate receptor subtype within the VTA and CeA that regulates binge-like EtOH drinking. Interestingly, inhibition of OX1Rs did not affect binge-like sucrose intake, which suggests that these OX circuits are specific for EtOH consumption. CONCLUSIONS: As a whole, these data suggest that the VTA and CeA are important regions in which OX regulates binge-like EtOH drinking behavior. Moreover, these findings identify OXR antagonists as a potential treatment option that may be used to ameliorate problematic drinking behavior while leaving responding to natural rewards relatively intact.
Authors: James R Shoblock; Natalie Welty; Leah Aluisio; Ian Fraser; S Timothy Motley; Kirsten Morton; James Palmer; Pascal Bonaventure; Nicholas I Carruthers; Timothy W Lovenberg; Jamin Boggs; Ruggero Galici Journal: Psychopharmacology (Berl) Date: 2010-12-22 Impact factor: 4.530
Authors: Morgan H James; Janine L Charnley; Emily M Levi; Emma Jones; Jiann Wei Yeoh; Doug W Smith; Christopher V Dayas Journal: Int J Neuropsychopharmacol Date: 2011-03-29 Impact factor: 5.176
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: Morgan H James; Jennifer E Fragale; Shayna L O'Connor; Benjamin A Zimmer; Gary Aston-Jones Journal: Neuropharmacology Date: 2020-10-19 Impact factor: 5.250
Authors: Sonia Aroni; Rosa A M Marino; Kasey S Girven; James M Irving; Joseph F Cheer; Dennis R Sparta Journal: Neuropharmacology Date: 2021-03-17 Impact factor: 5.250
Authors: Elizabeth M Avegno; Chelsea R Kasten; William B Snyder; Leslie K Kelley; Thomas D Lobell; Taylor J Templeton; Michael Constans; Tiffany A Wills; Jason W Middleton; Nicholas W Gilpin Journal: Addict Biol Date: 2020-12-16 Impact factor: 4.280