β1 adrenergic receptors interact with the ghrelin system to mediate binge drinking in a mouse model of AUD

Authors

• RS Richardson
• GF Koob
• LFVendruscolo
• L Leggio

Abstract

Alcohol use disorder (AUD) and binge drinking are highly prevalent public health issues. Studies show that the stomach-derived peptide ghrelin is implicated in alcohol-related outcomes. Ghrelin receptors (GHSR) are expressed in the brain and periphery. We previously found that intraperitoneal and intracerebroventricular administration of GHSR antagonists reduced intake in the Drinking-in-the-Dark mouse model of binge drinking, whereas sequestering circulating ghrelin did not. We hypothesize that central GHSRs drive binge drinking independently of peripheral ghrelin. To investigate this hypothesis, we targeted β-1 adrenergic receptors (β1ARs), which are required for stress and fasting-induced ghrelin release. The involvement of β1AR has not been addressed in a model of alcohol binge drinking; within the context of ghrelin-alcohol signaling; through the lens of central vs. peripheral signaling; or in subjects of both sexes. We hypothesized that β1AR blockade would not effect alcohol drinking. We administered two β1AR blockers intraperitoneally: atenolol (AT, peripherally restricted) and metoprolol (MT, brain permeable). MT but not AT decreased alcohol intake. Co-administration of AT or MT with JMV2959 (GHSR antagonist) or with PF-5190457 (inverse agonist) decreased intake. MT and JMV2929 had an additive effect. Finally, blood measurements indicate that AT and MT decrease blood ghrelin levels. No sex differences were observed. These results suggest that central but not peripheral β1ARs drive binge-like alcohol drinking. Also, β1AR blockade blocks ghrelin secretion and depletes ghrelin levels. Finally, blockade of β1AR does not prevent GHSR antagonists from decreasing drinking. β1ARs and GHSRs represent possible targets for therapeutic intervention for AUD, including potential additive effects.

Scientific Focus Area: Neuroscience

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