GHSR blockade, but not reduction of peripherally circulating ghrelin via β1-adrenergic receptor antagonism, decreases binge-like alcohol drinking in mice

Study Author Rani Richardson

Featured Paper of the Month – February 2025

Published in Molecular Psychiatry by Rani Richardson, Leandro Vendruscolo, and Lorenzo Leggio of the NIDA IRP.

Summary

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 β₁-adrenergic receptors (β₁ARs) using atenolol (peripherally restricted) and metoprolol (brain permeable). Both compounds robustly decreased plasma ghrelin levels. Also, direct brain administration of atenolol had no effect on peripheral endogenous ghrelin levels. However, only metoprolol, but not atenolol, decreased binge-like alcohol drinking. These results suggest that GHSRs rather than peripheral endogenous ghrelin is involved in binge-like alcohol drinking. They also suggest that central β₁ARs drive binge-like alcohol drinking. Thus, GHSRs and β₁ARs represent possible targets for therapeutic intervention for AUD, including the potential combination of drugs that target these two systems.

Publication Information

Richardson, Rani S; Kryszak, Lindsay A; Vendruscolo, Janaina C M; Koob, George F; Vendruscolo, Leandro F; Leggio, Lorenzo

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

In: Mol Psychiatry, 2024, ISSN: 1476-5578.

Abstract | Links

@article{pmid39232198,

title = {GHSR blockade, but not reduction of peripherally circulating ghrelin via β-adrenergic receptor antagonism, decreases binge-like alcohol drinking in mice},

author = {Rani S Richardson and Lindsay A Kryszak and Janaina C M Vendruscolo and George F Koob and Leandro F Vendruscolo and Lorenzo Leggio},

url = {https://pubmed.ncbi.nlm.nih.gov/39232198/},

doi = {10.1038/s41380-024-02713-3},

issn = {1476-5578},

year  = {2024},

date = {2024-09-01},

urldate = {2024-09-01},

journal = {Mol Psychiatry},

abstract = {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-adrenergic receptors (βARs), which are required for peripheral ghrelin release, and combined them with GHSR blockers. We found that both systemic βAR 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 βAR 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 βARs represent possible targets for therapeutic intervention for AUD, including the potential combination of drugs that target these two systems.},

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pubstate = {published},

tppubtype = {article}

}