TY - JOUR
T1 - A closer look at alcohol-induced changes in the ghrelin system
T2 - novel insights from preclinical and clinical data
AU - Deschaine, Sara L.
AU - Farokhnia, Mehdi
AU - Gregory-Flores, Adriana
AU - Zallar, Lia J.
AU - You, Zhi Bing
AU - Sun, Hui
AU - Harvey, Deon M.
AU - Marchette, Renata C.N.
AU - Tunstall, Brendan J.
AU - Mani, Bharath K.
AU - Moose, Jacob E.
AU - Lee, Mary R.
AU - Gardner, Eliot
AU - Akhlaghi, Fatemeh
AU - Roberto, Marisa
AU - Hougland, James L.
AU - Zigman, Jeffrey M.
AU - Koob, George F.
AU - Vendruscolo, Leandro F.
AU - Leggio, Lorenzo
N1 - Funding Information:
We thank the clinical and research staff involved in patient care, data collection/analysis, and technical support in the joint NIDA/NIAAA Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, in the NIAAA clinical program of the Division of Intramural Clinical and Biological Research (DICBR) (in particular the NIAAA Office of the Clinical Director and the NIAA Clinical Core Laboratory), at the NIH Clinical Center (Departments of Nursing, Nutrition, and Pharmacy), and in the Clinical Pharmacokinetics Research Laboratory at the University of Rhode Island. We would also like to thank Dr. Melanie Schwandt (Office of the Clinical Director, NIAAA) for data management. We would like to thank Dr. Vijay Ramchandani (Section on Human Psychopharmacology, NIAAA DICBR) and Dr. Reza Momenan (Clinical NeuroImaging Research Core, NIAAA DICBR) for their support in the execution of the parent studies from which these analyses stemmed. The authors would also like to express their gratitude to the participants who took part in these studies. We would like to thank the members of the Neurobiology of Addiction Section, the Transgenic Breeding Facility, and the Genetic Engineering and Viral Vector Core in the Intramural Research Program at NIDA/NIH involved in animal care and technical support. Finally, the authors would like to thank Ms. Donna Sheedy and Dr. Jillian Kril from the New South Wales Tissue Resource Centre (NSWBTRC) at the University of Sydney, Australia, for providing the human post‐mortem brain tissue for this project. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The human laboratory studies were supported by the NIH intramural funding ZIA‐DA‐000635 and ZIA‐AA000218 (Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section—PI: LL), jointly supported by the NIDA Intramural Research Program and the NIAAA Division of Intramural Clinical and Biological Research. The rodent studies were supported by the NIDA IRP Neurobiology of Addiction Section (PI: GFK) and by the NIDA/NIAAA joint Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section (PI: LL). The development of the Computerized Alcohol Infusion System (CAIS) software used in the IV ghrelin study was supported by Dr. Vijay Ramchandani's Section on Human Psychopharmacology in the NIAAA Division of Intramural Clinical and Biological Research and by the NIAAA‐funded Indiana Alcohol Research Center (AA007611). The PF‐5190457 phase 1b study received additional funding from the National Center for Advancing Translational Sciences (NCATS), under an UH2/UH3 grant (TR000963—PIs: LL and FA). Pfizer kindly provided the PF‐5190457 compound under the NCATS grant UH2/UH3‐TR000963. Pfizer did not have any role in the study design, execution or interpretation of the results, and this publication does not necessarily represent the official views of Pfizer. The baclofen study received additional finding from the Brain and Behavior Research Foundation (BBRF; formerly NARSAD) grant number 17325 (PI: LL). Brain tissues were received from the New South Wales Brain Tissue Resource Centre (NSWBTRC) at the University of Sydney, which is supported by NIAAA under Award Number R28AA012725 and Neuroscience Research Australia. The GOAT enzyme activity studies were supported by NIGMS under grant R01GM134102 (PI: JLH). MF and RCNM were fellows of the Center for Compulsive Behaviors at NIH. BJT was additionally supported by NIH award DA048530. The experiments in gastric mucosal cells were supported by a NIH extramural grant R01DK103884 (PI: JMZ). ex vivo
Publisher Copyright:
Published 2021. This article is a U.S. Government work and is in the public domain in the USA.
PY - 2022/1
Y1 - 2022/1
N2 - Ghrelin is a gastric-derived peptide hormone with demonstrated impact on alcohol intake and craving, but the reverse side of this bidirectional link, that is, the effects of alcohol on the ghrelin system, remains to be fully established. To further characterize this relationship, we examined (1) ghrelin levels via secondary analysis of human laboratory alcohol administration experiments with heavy-drinking participants; (2) expression of ghrelin, ghrelin receptor, and ghrelin-O-acyltransferase (GOAT) genes (GHRL, GHSR, and MBOAT4, respectively) in post-mortem brain tissue from individuals with alcohol use disorder (AUD) versus controls; (3) ghrelin levels in Ghsr knockout and wild-type rats following intraperitoneal (i.p.) alcohol administration; (4) effect of alcohol on ghrelin secretion from gastric mucosa cells ex vivo and GOAT enzymatic activity in vitro; and (5) ghrelin levels in rats following i.p. alcohol administration versus a calorically equivalent non-alcoholic sucrose solution. Acyl- and total-ghrelin levels decreased following acute alcohol administration in humans, but AUD was not associated with changes in central expression of ghrelin system genes in post-mortem tissue. In rats, alcohol decreased acyl-ghrelin, but not des-acyl-ghrelin, in both Ghsr knockout and wild-type rats. No dose-dependent effects of alcohol were observed on acyl-ghrelin secretion from gastric mucosa cells or on GOAT acylation activity. Lastly, alcohol and sucrose produced distinct effects on ghrelin in rats despite equivalent caloric value. Our findings suggest that alcohol acutely decreases peripheral ghrelin concentrations in vivo, but not in proportion to alcohol's caloric value or through direct interaction with ghrelin-secreting gastric mucosal cells, the ghrelin receptor, or the GOAT enzyme.
AB - Ghrelin is a gastric-derived peptide hormone with demonstrated impact on alcohol intake and craving, but the reverse side of this bidirectional link, that is, the effects of alcohol on the ghrelin system, remains to be fully established. To further characterize this relationship, we examined (1) ghrelin levels via secondary analysis of human laboratory alcohol administration experiments with heavy-drinking participants; (2) expression of ghrelin, ghrelin receptor, and ghrelin-O-acyltransferase (GOAT) genes (GHRL, GHSR, and MBOAT4, respectively) in post-mortem brain tissue from individuals with alcohol use disorder (AUD) versus controls; (3) ghrelin levels in Ghsr knockout and wild-type rats following intraperitoneal (i.p.) alcohol administration; (4) effect of alcohol on ghrelin secretion from gastric mucosa cells ex vivo and GOAT enzymatic activity in vitro; and (5) ghrelin levels in rats following i.p. alcohol administration versus a calorically equivalent non-alcoholic sucrose solution. Acyl- and total-ghrelin levels decreased following acute alcohol administration in humans, but AUD was not associated with changes in central expression of ghrelin system genes in post-mortem tissue. In rats, alcohol decreased acyl-ghrelin, but not des-acyl-ghrelin, in both Ghsr knockout and wild-type rats. No dose-dependent effects of alcohol were observed on acyl-ghrelin secretion from gastric mucosa cells or on GOAT acylation activity. Lastly, alcohol and sucrose produced distinct effects on ghrelin in rats despite equivalent caloric value. Our findings suggest that alcohol acutely decreases peripheral ghrelin concentrations in vivo, but not in proportion to alcohol's caloric value or through direct interaction with ghrelin-secreting gastric mucosal cells, the ghrelin receptor, or the GOAT enzyme.
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U2 - 10.1111/adb.13033
DO - 10.1111/adb.13033
M3 - Article
C2 - 33908131
AN - SCOPUS:85109838689
SN - 1355-6215
VL - 27
JO - Addiction Biology
JF - Addiction Biology
IS - 1
M1 - e13033
ER -