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), which are required for peripheral ghrelin release, and combined them with GHSR blockers. We found that both systemic β₁AR 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 β₁AR 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 β₁ARs represent possible targets for therapeutic intervention for AUD, including the potential combination of drugs that target these two systems.

酒精使用障碍（AUD）和酗酒是非常普遍的公共卫生问题。胃源性肽饥饿素及其受体生长激素促分泌素受体 (GHSR) 均在大脑和外周表达，与酒精相关的结果有关。我们之前发现，全身和中枢施用 GHSR 拮抗剂可以减少暴饮暴食，而生长素释放肽疫苗却不能。因此，我们假设中枢 GHSR 独立于外周 ghrelin 驱动酗酒。为了研究这一假设，我们拮抗了外周生长素释放肽释放所需的_β1-肾上腺素受体（ _β1AR ），并将其与GHSR阻滞剂联合使用。我们发现，阿替洛尔（外周限制性）和美托洛尔（脑渗透性）的全身_β1 AR 拮抗作用均显着降低血浆生长素释放肽水平。此外，ICV给予阿替洛尔对外周内源性生长素释放肽水平没有影响。然而，只有美托洛尔能够减少暴饮暴食，而阿替洛尔则不然。 β ₁ AR 拮抗作用也不能阻止 GHSR 阻滞剂 JMV2959 和 PF-5190457 在减少酗酒方面的作用。这些结果表明 GHSR 而不是外周内源性 ghrelin 与暴饮暴食有关。因此，GHSR 和 β ₁ AR 代表了 AUD 治疗干预的可能目标，包括针对这两个系统的药物的潜在组合。