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The Amygdala Noradrenergic System Is Compromised With Alcohol Use Disorder.

Authors :: Varodayan FP
Patel RR
Matzeu A
Wolfe SA
Curley DE
Khom S
Gandhi PJ
Rodriguez L
Bajo M
D'Ambrosio S
Sun H
Kerr TM
Gonzales RA
Leggio L
Natividad LA
Haass-Koffler CL
Martin-Fardon R
Roberto M
Source :: Biological psychiatry [Biol Psychiatry] 2022 Jun 15; Vol. 91 (12), pp. 1008-1018. Date of Electronic Publication: 2022 Apr 13.
Publication Year :: 2022
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.<br />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were housed under control conditions, subjected to chronic intermittent ethanol vapor exposure to induce dependence, or withdrawn from chronic intermittent ethanol vapor exposure for 2 weeks, and ex vivo electrophysiology, biochemistry (catecholamine quantification by high-performance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 α <subscript>1</subscript> <subscript>B</subscript> , β <subscript>1</subscript> , and β <subscript>2</subscript> adrenergic receptors in human postmortem brain tissue from men diagnosed with AUD and matched control subjects.<br />Results: We found that α <subscript>1</subscript> 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 α <subscript>1</subscript> <subscript>B</subscript> receptor messenger RNA in the amygdala of humans with AUD.<br />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.<br /> (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)