Indiana University School of Medicine, Department of Psychiatry, Indianapolis, IN 46202, USA.
Indiana University School of Medicine, Department of Psychiatry, Indianapolis, IN 46202, USA.
Neuropharmacology. 2023 Aug 15;234:109545. doi: 10.1016/j.neuropharm.2023.109545. Epub 2023 Apr 25.
Alcohol Use Disorders (AUD) is characterized by compulsion-like alcohol drinking (CLAD), where intake despite negative consequences can be a major clinical obstacle. With few treatment options available for AUD, there is a significant need for novel therapies. The noradrenergic system is an important hub for regulating stress responses and maladaptive drives for alcohol. Studies have shown that drugs targeting α1 adrenenergic receptors (ARs) may represent a pharmacological treatment for pathological drinking. However, the involvement of β ARs for treating human drinking has received scant investigation, and thus we sought to provide pre-clinical validation for possible AR utility for CLAD by analyzing whether β AR antagonists propranolol (β1/2), betaxolol (β1), and ICI, 118,551 (β2) impacted CLAD and alcohol-only drinking (AOD) in male Wistar rats. We found that the highest dose of propranolol tested systemically (10 mg/kg) reduced alcohol drinking, while 5 mg/kg propranolol reduced drinking with a trend to impact CLAD more than AOD, and with no effects of 2.5 mg/kg. Betaxolol (2.5 mg/kg) also decreased drinking, while ICI 118.551 had no effects. Also, while AR compounds might have utility for AUD, they can also lead to undesirable side effects. Here, a combination of ineffective doses of propranolol and prazosin reduced both CLAD and AOD. Finally, we investigated the effect of propranolol and betaxolol in two brain areas related to pathological drinking, the anterior insula (aINS) and medial prefrontal cortex (mPFC). Surprisingly, propranolol (1-10 μg) in aINS or mPFC did not affect CLAD or AOD. Together, our findings provide new pharmacological insights into noradrenergic regulation of alcohol consumption, which may inform AUD therapy.
酒精使用障碍（AUD）的特征是强迫性饮酒（CLAD），即使有负面后果，仍持续饮酒，这可能是临床治疗的一大障碍。由于 AUD 的治疗选择有限，因此非常需要新的治疗方法。去甲肾上腺素能系统是调节应激反应和酒精适应不良驱动的重要枢纽。研究表明，靶向α1肾上腺素能受体（ARs）的药物可能是治疗病理性饮酒的一种药理学治疗方法。然而，β AR 治疗人类饮酒的作用却很少受到关注，因此我们试图通过分析β AR 拮抗剂普萘洛尔（β1/2）、倍他洛尔（β1）和 ICI 118,551（β2）是否会影响雄性 Wistar 大鼠的 CLAD 和仅饮酒（AOD），为 AR 治疗 CLAD 提供临床前验证。我们发现，系统给予的最高剂量的普萘洛尔（10 mg/kg）可减少酒精摄入，而 5 mg/kg 的普萘洛尔可减少饮酒，且有减少 CLAD 的趋势，对 AOD 的影响较小，而 2.5 mg/kg 的普萘洛尔无影响。倍他洛尔（2.5 mg/kg）也可减少饮酒，而 ICI 118,551 则无影响。此外，尽管 AR 化合物可能对 AUD 有效，但也可能导致不良的副作用。在此，普萘洛尔和哌唑嗪的无效剂量组合可同时减少 CLAD 和 AOD。最后，我们研究了普萘洛尔和倍他洛尔在与病理性饮酒相关的两个脑区（前岛叶（aINS）和内侧前额叶皮质（mPFC））中的作用。令人惊讶的是，aINS 或 mPFC 中的普萘洛尔（1-10 μg）不影响 CLAD 或 AOD。总之，我们的研究结果为去甲肾上腺素能系统调节酒精摄入提供了新的药理学见解，可能为 AUD 治疗提供参考。
