Effects of metformin on binge-like ethanol drinking and adenosine monophosphate kinase signaling in inbred high drinking in the dark line 1 mice

Background

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.

Methods

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).

Results

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.

Conclusions

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.