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Exogenous ghrelin administration increases alcohol self-administration and modulates brain functional activity in heavy-drinking alcohol-dependent individuals

Abstract

Preclinical evidence suggests that ghrelin, a peptide synthesized by endocrine cells of the stomach and a key component of the gut–brain axis, is involved in alcohol seeking as it modulates both central reward and stress pathways. However, whether and how ghrelin administration may impact alcohol intake in humans is not clear. For, we believe, the first time, this was investigated in the present randomized, crossover, double-blind, placebo-controlled, human laboratory study. Participants were non-treatment-seeking alcohol-dependent heavy-drinking individuals. A 10-min loading dose of intravenous ghrelin/placebo (3 mcg kg−1) followed by a continuous ghrelin/placebo infusion (16.9 ng/kg/min) was administered. During a progressive-ratio alcohol self-administration experiment, participants could press a button to receive intravenous alcohol using the Computerized Alcohol Infusion System. In another experiment, brain functional magnetic resonance imaging was conducted while participants performed a task to gain points for alcohol, food or no reward. Results showed that intravenous ghrelin, compared to placebo, significantly increased the number of alcohol infusions self-administered (percent change: 24.97±10.65, P=0.04, Cohen’s d=0.74). Participants were also significantly faster to initiate alcohol self-administration when they received ghrelin, compared to placebo (P=0.03). The relationships between breath alcohol concentration and subjective effects of alcohol were also moderated by ghrelin administration. Neuroimaging data showed that ghrelin increased the alcohol-related signal in the amygdala (P=0.01) and modulated the food-related signal in the medial orbitofrontal cortex (P=0.01) and nucleus accumbens (P=0.08). These data indicate that ghrelin signaling affects alcohol seeking in humans and should be further investigated as a promising target for developing novel medications for alcohol use disorder.

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Acknowledgments

We thank the clinical and research staff involved in data collection and support at the National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, that is, the NIAAA/NIDA Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology and the NIAAA clinical intramural program. We also thank the clinical and research staff involved in data collection, patient care and clinical/technical support at the following NIH Clinical Center Departments: Nursing (in particular, the nurses of the 1SE Inpatient Unit and of the 1-HALC 1SE Outpatient Clinic), Nutrition (in particular LT Kelly Ratteree, MPH, RDN and CDR Merel Kozlosky, MS, RD) and Pharmacy. Furthermore, we thank Ms Karen Smith from the NIH Library for bibliographic assistance. We also thank the deceased and profoundly missed Daniel W. Hommer, MD, for his critical input and guidance during the early phase of development of the fMRI experiment of this protocol. Finally, we would like to express our gratitude to the participants who took part in this study.

This work was supported by National Institutes of Health (NIH) intramural funding ZIA-AA000218 (Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology; PI: Dr Lorenzo Leggio), jointly supported by the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Intramural Research Program of the National Institute on Drug Abuse (NIDA). The development of the Computerized Alcohol Infusion System (CAIS) software was supported by the NIAAA-funded Indiana Alcohol Research Center (AA007611).

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The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors report no biomedical financial interests or potential conflicts of interest.

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Farokhnia, M., Grodin, E.N., Lee, M.R. et al. Exogenous ghrelin administration increases alcohol self-administration and modulates brain functional activity in heavy-drinking alcohol-dependent individuals. Mol Psychiatry 23, 2029–2038 (2018). https://doi.org/10.1038/mp.2017.226

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