GHSR blockade, but not reduction of peripherally circulating ghrelin via β 1 -adrenergic receptor antagonism, decreases binge-like alcohol drinking in mice.

Autor: Richardson RS; Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, MD, USA.; Neurobiology of Addiction Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.; University of North Carolina School of Medicine MD/PhD Program, University of North Carolina, Chapel Hill, NC, USA.; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA.; Stress and Addiction Neuroscience Unit, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD, USA., Kryszak LA; National Institute on Drug Abuse Intramural Research Program Translational Analytical Core, National Institutes of Health, Baltimore, MD, USA., Vendruscolo JCM; Neurobiology of Addiction Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.; Stress and Addiction Neuroscience Unit, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD, USA., Koob GF; Neurobiology of Addiction Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, USA., Vendruscolo LF; Stress and Addiction Neuroscience Unit, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD, USA. leandro.vendruscolo@nih.gov., Leggio L; Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, MD, USA. lorenzo.leggio@nih.gov.; National Institute on Drug Abuse Intramural Research Program Translational Analytical Core, National Institutes of Health, Baltimore, MD, USA. lorenzo.leggio@nih.gov.; Department of Behavioral and Social Sciences, Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA. lorenzo.leggio@nih.gov.; Medication Development Program, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA. lorenzo.leggio@nih.gov.; Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA. lorenzo.leggio@nih.gov.; Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA. lorenzo.leggio@nih.gov.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2024 Sep 05. Date of Electronic Publication: 2024 Sep 05.
DOI: 10.1038/s41380-024-02713-3
Abstrakt: Alcohol use disorder (AUD) and binge drinking are highly prevalent public health issues. The stomach-derived peptide ghrelin, and its receptor, the growth hormone secretagogue receptor (GHSR), both of which are expressed in the brain and periphery, are implicated in alcohol-related outcomes. We previously found that systemic and central administration of GHSR antagonists reduced binge-like alcohol drinking, whereas a ghrelin vaccine did not. Thus, we hypothesized that central GHSR drives binge-like alcohol drinking independently of peripheral ghrelin. To investigate this hypothesis, we antagonized β 1 -adrenergic receptors (β 1 ARs), which are required for peripheral ghrelin release, and combined them with GHSR blockers. We found that both systemic β 1 AR antagonism with atenolol (peripherally restricted) and metoprolol (brain permeable) robustly decreased plasma ghrelin levels. Also, ICV administration of atenolol had no effect on peripheral endogenous ghrelin levels. However, only metoprolol, but not atenolol, decreased binge-like alcohol drinking. The β 1 AR antagonism also did not prevent the effects of the GHSR blockers JMV2959 and PF-5190457 in decreasing binge-like alcohol drinking. These results suggest that the GHSR rather than peripheral endogenous ghrelin is involved in binge-like alcohol drinking. Thus, GHSRs and β 1 ARs represent possible targets for therapeutic intervention for AUD, including the potential combination of drugs that target these two systems.
(© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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