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Excessive alcohol consumption, including binge drinking, is a common cause of fatty liver disease. Binge drinking rapidly induces hepatic steatosis, an early step in the pathogenesis of chronic liver injury. Despite its prevalence, the process by which excessive alcohol consumption promotes hepatic lipid accumulation remains unclear. Alcohol exerts potent effects on the brain, including hypothalamic neurons crucial for metabolic regulation. However, whether or not the brain plays a role in alcohol-induced hepatic steatosis is unknown. In the brain, alcohol increases extracellular levels of adenosine, a potent neuromodulator, and previous work implicates adenosine signaling as being important for the development of alcoholic fatty liver disease. Acute alcohol exposure also increases both the activity of agouti-related protein (AgRP)-expressing neurons and AgRP immunoreactivity. Here, we show that adenosine receptor A 2B signaling in the brain modulates the extent of alcohol-induced fatty liver in mice and that both the AgRP neuropeptide and the sympathetic nervous system are indispensable for hepatic steatosis induced by bingelike alcohol consumption. Together, these results indicate that the brain plays an integral role in alcohol-induced hepatic lipid accumulation and that central adenosine signaling, hypothalamic AgRP, and the sympathetic nervous system are crucial mediators of this process.

Background: Liver damage is a serious and sometimes fatal consequence of long-term alcohol intake, which progresses from early-stage fatty liver (steatosis) to later-stage steatohepatitis with inflammation and fibrosis/necrosis. However, very little is known about earlier stages of liver disruption that may occur in problem drinkers, those who drink excessively but are not dependent on alcohol., Methods: We examined how repeated binge-like alcohol drinking in C57BL/6 mice altered liver function, as compared with a single binge-intake session and with repeated moderate alcohol consumption. We measured a number of markers associated with early- and later-stage liver disruption, including liver steatosis, measures of liver cytochrome P4502E1 (CYP2E1) and alcohol dehydrogenase (ADH), alcohol metabolism, expression of cytokine mRNA, accumulation of 4-hydroxynonenal (4-HNE) as an indicator of oxidative stress, and alanine transaminase/aspartate transaminase as a measure of hepatocyte injury., Results: Importantly, repeated binge-like alcohol drinking increased triglyceride levels in the liver and plasma, and increased lipid droplets in the liver, indicators of steatosis. In contrast, a single binge-intake session or repeated moderate alcohol consumption did not alter triglyceride levels. In addition, alcohol exposure can increase rates of alcohol metabolism through CYP2E1 and ADH, which can potentially increase oxidative stress and liver dysfunction. Intermittent, excessive alcohol intake increased liver CYP2E1 mRNA, protein, and activity, as well as ADH mRNA and activity. Furthermore, repeated, binge-like drinking, but not a single binge or moderate drinking, increased alcohol metabolism. Finally, repeated, excessive intake transiently elevated mRNA for the proinflammatory cytokine IL-1B and 4-HNE levels, but did not alter markers of later-stage liver hepatocyte injury., Conclusions: Together, we provide data suggesting that even relatively limited binge-like alcohol drinking can lead to disruptions in liver function, which might facilitate the transition to more severe forms of liver damage., (Copyright © 2017 by the Research Society on Alcoholism.)

Early binge-like alcohol drinking may promote the development of hazardous intake. However, the enduring cellular alterations following the first experience with alcohol consumption are not fully understood. We found that the first binge-drinking alcohol session produced enduring enhancement of excitatory synaptic transmission onto dopamine D1 receptor-expressing neurons (D1+ neurons) in the nucleus accumbens (NAc) shell but not the core in mice, which required D1 receptors (D1Rs) and mechanistic target of rapamycin complex 1 (mTORC1). Furthermore, inhibition of mTORC1 activity during the first alcohol drinking session reduced alcohol consumption and preference of a subsequent drinking session. mTORC1 is critically involved in RNA-to-protein translation, and we found that the first alcohol session rapidly activated mTORC1 in NAc shell D1+ neurons and increased synaptic expression of the AMPAR subunit GluA1 and the scaffolding protein Homer. Finally, D1R stimulation alone was sufficient to activate mTORC1 in the NAc to promote mTORC1-dependent translation of the synaptic proteins GluA1 and Homer. Together, our results indicate that the first alcohol drinking session induces synaptic plasticity in NAc D1+ neurons via enhanced mTORC1-dependent translation of proteins involved in excitatory synaptic transmission that in turn drives the reinforcement learning associated with the first alcohol experience. Thus, the alcohol-dependent D1R/mTORC1-mediated increase in synaptic function in the NAc may reflect a neural imprint of alcohol's reinforcing properties, which could promote subsequent alcohol intake. Significance statement: Consuming alcohol for the first time is a learning event that drives further drinking. Here, we identified a mechanism that may underlie the reinforcing learning associated with the initial alcohol experience. We show that the first alcohol experience induces a persistent enhancement of excitatory synaptic transmission on NAc shell D1+ neurons, which is dependent on D1R and mTORC1. We also find that mTORC1 is necessary for the sustained alcohol consumption and preference across the initial drinking sessions. The first alcohol binge activates mTORC1 in NAc D1+ neurons and increases levels of synaptic proteins involved in glutamatergic signaling. Thus, the D1R/mTORC1-dependent plasticity following the first alcohol exposure may be a critical cellular component of reinforcement learning.

Excessive, binge alcohol drinking is a potent and pernicious obstacle to treating alcohol use disorder (AUD), and heavy-drinking humans are responsible for much of the substantial costs and harms of AUD. Thus, identifying key mechanisms that drive intake in higher-drinking individuals may provide important, translationally useful therapeutic interventions. Orexin-1-receptors (Ox1Rs) promote states of high motivation, and studies with systemic Ox1R inhibition suggest a particular role in individuals with higher intake levels. However, little has been known about circuits where Ox1Rs promote pathological intake, especially excessive alcohol consumption. We previously discovered that binge alcohol drinking requires Ox1Rs in medial nucleus accumbens shell (Shell), using two-bottle-choice Drinking-in-the-Dark (2bc-DID) in adult, male C57BL/6 mice. Here, we show that Shell Ox1Rs promoted intake during intermittent-access alcohol drinking as well as 2bc-DID, and that Shell inhibition with muscimol/baclofen also suppressed 2bc-DID intake. Importantly, with this large data set, we were able to demonstrate that Shell Ox1Rs and overall activity were particularly important for driving alcohol consumption in higher-drinking individuals, with little overall impact in moderate drinkers. Shell inhibition results were compared with control data combined from drug treatments that did not reduce intake, including NMDAR or PKC inhibition in Shell, Ox1R inhibition in accumbens core, and systemic inhibition of dopamine-1 receptors; these were used to understand whether more specific Shell Ox1R contributions in higher drinkers might simply result from intrinsic variability in mouse drinking. Ineffectiveness of Shell inhibition in moderate-drinkers was not due to a floor effect, since systemic baclofen reduced alcohol drinking regardless of basal intake levels, without altering concurrent water intake or saccharin consumption. Finally, alcohol intake in the first exposure predicted consumption levels weeks later, suggesting that intake level may be a stable trait in each individual. Together, our studies indicate that Shell Ox1Rs are critical mediators of binge alcohol intake in higher-drinking individuals, with little net contribution to alcohol drinking in more moderate bingers, and that targeting Ox1Rs may substantially reduce AUD-related harms. [ABSTRACT FROM AUTHOR]