Grigsby Kolter, Palacios Jonathan, Chan Amy E, Spencer Sade M, Ozburn Angela R
Research and Development Service, Portland Veterans Affairs Medical Center, Portland, Oregon, USA.
Department of Behavioral Neuroscience, Portland Alcohol Research Center, Oregon Health and Science University, Portland, Oregon, USA.
Alcohol Clin Exp Res (Hoboken). 2024 Dec;48(12):2269-2280. doi: 10.1111/acer.15460. Epub 2024 Nov 26.
Adenosine monophosphate-activated protein kinase (AMPK) signaling plays a vital role in regulating cellular metabolism and energy throughout the body. Ethanol and cocaine both reduce AMPK activity in addiction-related brain regions. Though AMPK activation has been found to reduce cocaine seeking, its role in harmful drinking and alcohol use disorder (AUD) progression remains unclear. We asked whether metformin, a first-line type 2 diabetes medication that targets AMPK, can reduce binge-like ethanol intake in inbred High Drinking in the Dark Line-1 (iHDID-1) mice, a genetic risk model for drinking to intoxication. We then determined whether metformin altered ethanol clearance in iHDID-1 mice. Next, we tested whether metformin and/or ethanol altered AMPK signaling in the nucleus accumbens (NAc), a brain region critically important for harmful drinking.
We measured the effects of metformin [0 or 250 mg/kg; intraperitoneal injection (i.p.)] on binge-like ethanol intake in separate acute (Experiment 1) and chronic (Experiment 3A) drinking studies (n = 6-8 iHDID-1 mice/sex/treatment/experiment). The effect of metformin (0 or 250 mg/kg) on ethanol (2.0 g/kg, i.p.) clearance was tested in iHDID-1 mice (Experiment 2; n = 7-9/sex/treatment). Lastly, we measured NAc AMPK and phosphorylated AMPK (pAMPK) levels in response to chronic ethanol (or water) drinking (n = 6 iHDID-1 mice/sex/treatment/fluid type; Experiment 3B) and an intoxicating dose of ethanol (2.0 g/kg; i.p.; Experiment 4).
Metformin reduced binge-like ethanol drinking intake in acute and chronic studies in both male and female iHDID-1 mice (p's < 0.05). We found no significant changes in ethanol clearance in response to metformin. Moreover, no differences in AMPK or pAMPK levels in the NAc were observed with either ethanol or metformin.
These findings provide early support for the repurposing of metformin, an affordable and safe diabetes medication, to reduce harmful ethanol intake and lay a foundation for testing its efficacy to treat individuals with AUD.
腺苷单磷酸激活蛋白激酶（AMPK）信号传导在调节全身细胞代谢和能量方面起着至关重要的作用。乙醇和可卡因都会降低成瘾相关脑区的AMPK活性。尽管已发现激活AMPK可减少对可卡因的觅求，但它在有害饮酒和酒精使用障碍（AUD）进展中的作用仍不清楚。我们研究了二甲双胍（一种靶向AMPK的一线2型糖尿病药物）是否能减少近交系黑暗中高饮系-1（iHDID-1）小鼠的暴饮样乙醇摄入量，iHDID-1小鼠是一种因饮酒致醉的遗传风险模型。然后我们确定二甲双胍是否改变了iHDID-1小鼠的乙醇清除率。接下来，我们测试了二甲双胍和/或乙醇是否改变了伏隔核（NAc）中的AMPK信号传导，伏隔核是对有害饮酒至关重要的脑区。
我们在单独的急性（实验1）和慢性（实验3A）饮酒研究中测量了二甲双胍[0或250mg/kg；腹腔注射（i.p.）]对暴饮样乙醇摄入量的影响（n = 6 - 8只iHDID-1小鼠/性别/处理/实验）。在iHDID-1小鼠中测试了二甲双胍（0或250mg/kg）对乙醇（2.0g/kg，i.p.）清除率的影响（实验2；n = 7 - 9只/性别/处理）。最后，我们测量了慢性乙醇（或水）饮用（n = 6只iHDID-1小鼠/性别/处理/液体类型；实验3B）和中毒剂量乙醇（2.0g/kg；i.p.；实验4）后伏隔核中AMPK和磷酸化AMPK（pAMPK）的水平。
在急性和慢性研究中，二甲双胍均降低了雄性和雌性iHDID-1小鼠的暴饮样乙醇饮用量（p值<0.05）。我们发现二甲双胍对乙醇清除率无显著影响。此外，乙醇或二甲双胍对伏隔核中AMPK或pAMPK水平均无差异。
这些发现为重新利用二甲双胍（一种价格低廉且安全的糖尿病药物）来减少有害乙醇摄入量提供了早期支持，并为测试其治疗AUD患者的疗效奠定了基础。
