Florence P Varodayan1, Reesha R Patel2, Alessandra Matzeu3, Sarah A Wolfe3, Dallece E Curley4, Sophia Khom3, Pauravi J Gandhi3, Larry Rodriguez3, Michal Bajo3, Shannon D'Ambrosio3, Hui Sun5, Tony M Kerr6, Rueben A Gonzales6, Lorenzo Leggio7, Luis A Natividad6, Carolina L Haass-Koffler8, Rémi Martin-Fardon3, Marisa Roberto9. 1. Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California; Developmental Exposure Alcohol Research Center and Behavioral Neuroscience Program, Department of Psychology, Binghamton University, State University of New York, Binghamton, New York. 2. Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California; Systems Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, California. 3. Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California. 4. Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, School of Public Health, Brown University, Providence, Rhode Island; Neuroscience Graduate Program, Department of Neuroscience, Brown University, Providence, Rhode Island. 5. Clinical Core Laboratory, Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland. 6. College of Pharmacy, Division of Pharmacology and Toxicology, University of Texas at Austin, Austin, Texas. 7. Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, School of Public Health, Brown University, Providence, Rhode Island; Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland; Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland; Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland; Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland; Department of Neuroscience, Georgetown University Medical Center, Washington, DC. 8. Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, School of Public Health, Brown University, Providence, Rhode Island; Department of Psychiatry and Human Behavior, Warren Alpert Medical School, Brown University, Providence, Rhode Island; Carney Institute for Brain Science, Brown University, Providence, Rhode Island; Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland; Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland. 9. Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California. Electronic address: mroberto@scripps.edu.
Abstract
BACKGROUND: Alcohol use disorder (AUD) is a leading preventable cause of death. The central amygdala (CeA) is a hub for stress and AUD, while dysfunction of the noradrenaline stress system is implicated in AUD relapse. METHODS: Here, we investigated whether alcohol (ethanol) dependence and protracted withdrawal alter noradrenergic regulation of the amygdala in rodents and humans. Male adult rats were housed under control conditions, subjected to chronic intermittent ethanol vapor exposure to induce dependence, or withdrawn from chronic intermittent ethanol vapor exposure for 2 weeks, and ex vivo electrophysiology, biochemistry (catecholamine quantification by high-performance liquid chromatography), in situ hybridization, and behavioral brain-site specific pharmacology studies were performed. We also used real-time quantitative polymerase chain reaction to assess gene expression of α1B, β1, and β2 adrenergic receptors in human postmortem brain tissue from men diagnosed with AUD and matched control subjects. RESULTS: We found that α1 receptors potentiate CeA GABAergic (gamma-aminobutyric acidergic) transmission and drive moderate alcohol intake in control rats. In dependent rats, β receptors disinhibit a subpopulation of CeA neurons, contributing to their excessive drinking. Withdrawal produces CeA functional recovery with no change in local noradrenaline tissue concentrations, although there are some long-lasting differences in the cellular patterns of adrenergic receptor messenger RNA expression. In addition, postmortem brain analyses reveal increased α1B receptor messenger RNA in the amygdala of humans with AUD. CONCLUSIONS: CeA adrenergic receptors are key neural substrates of AUD. Identification of these novel mechanisms that drive alcohol drinking, particularly during the alcohol-dependent state, supports ongoing new medication development for AUD.
BACKGROUND: Alcohol use disorder (AUD) is a leading preventable cause of death. The central amygdala (CeA) is a hub for stress and AUD, while dysfunction of the noradrenaline stress system is implicated in AUD relapse. METHODS: Here, we investigated whether alcohol (ethanol) dependence and protracted withdrawal alter noradrenergic regulation of the amygdala in rodents and humans. Male adult rats were housed under control conditions, subjected to chronic intermittent ethanol vapor exposure to induce dependence, or withdrawn from chronic intermittent ethanol vapor exposure for 2 weeks, and ex vivo electrophysiology, biochemistry (catecholamine quantification by high-performance liquid chromatography), in situ hybridization, and behavioral brain-site specific pharmacology studies were performed. We also used real-time quantitative polymerase chain reaction to assess gene expression of α1B, β1, and β2 adrenergic receptors in human postmortem brain tissue from men diagnosed with AUD and matched control subjects. RESULTS: We found that α1 receptors potentiate CeA GABAergic (gamma-aminobutyric acidergic) transmission and drive moderate alcohol intake in control rats. In dependent rats, β receptors disinhibit a subpopulation of CeA neurons, contributing to their excessive drinking. Withdrawal produces CeA functional recovery with no change in local noradrenaline tissue concentrations, although there are some long-lasting differences in the cellular patterns of adrenergic receptor messenger RNA expression. In addition, postmortem brain analyses reveal increased α1B receptor messenger RNA in the amygdala of humans with AUD. CONCLUSIONS: CeA adrenergic receptors are key neural substrates of AUD. Identification of these novel mechanisms that drive alcohol drinking, particularly during the alcohol-dependent state, supports ongoing new medication development for AUD.
Authors: George A Kenna; Carolina L Haass-Koffler; William H Zywiak; Steven M Edwards; Michael B Brickley; Robert M Swift; Lorenzo Leggio Journal: Addict Biol Date: 2015-06-02 Impact factor: 4.280
Authors: Terril L Verplaetse; Dennis D Rasmussen; Janice C Froehlich; Cristine L Czachowski Journal: Alcohol Clin Exp Res Date: 2011-10-07 Impact factor: 3.455
Authors: Rajita Sinha; Helen C Fox; Kwangik A Hong; Keri Bergquist; Zubin Bhagwagar; Kristen M Siedlarz Journal: Neuropsychopharmacology Date: 2008-06-18 Impact factor: 7.853
Authors: Larry Rodriguez; Dean Kirson; Sarah A Wolfe; Reesha R Patel; Florence P Varodayan; Angela E Snyder; Pauravi J Gandhi; Sophia Khom; Roman Vlkolinsky; Michal Bajo; Marisa Roberto Journal: Int J Mol Sci Date: 2022-07-16 Impact factor: 6.208