The Amygdala Noradrenergic System Is Compromised With Alcohol Use Disorder

Florence P Varodayan; Reesha R Patel; Alessandra Matzeu; Sarah A Wolfe; Dallece E Curley; Sophia Khom; Pauravi J Gandhi; Larry Rodriguez; Michal Bajo; Shannon D'Ambrosio; Hui Sun; Tony M Kerr; Rueben A Gonzales; Lorenzo Leggio; Luis A Natividad; Carolina L Haass-Koffler; Rémi Martin-Fardon; Marisa Roberto

doi:10.1016/j.biopsych.2022.02.006

The Amygdala Noradrenergic System Is Compromised With Alcohol Use Disorder

Biol Psychiatry. 2022 Jun 15;91(12):1008-1018. doi: 10.1016/j.biopsych.2022.02.006. Epub 2022 Apr 13.

Authors

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

Affiliations

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 α₁_B, 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 α₁_B 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.

Keywords: Adrenergic receptor; Ethanol; Norepinephrine/noradrenaline; Prazosin; Propranolol; Translation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural

MeSH terms

Alcohol Drinking
Alcoholism*
Animals
Central Amygdaloid Nucleus* / metabolism
Ethanol / pharmacology
Humans
Male
Norepinephrine
RNA, Messenger
Rats
Receptors, Adrenergic / metabolism

Substances

RNA, Messenger
Receptors, Adrenergic
Ethanol
Norepinephrine

Abstract

Publication types

MeSH terms

Substances

Grants and funding