by Dr. Mark Gold
Experts, analysts, and officials sometimes find certain mysteries of alcohol use disorder (AUD) frustrating. Wouldn’t it be so much easier if we could find a single, or even primary, cause of the condition? Or if we could know with certainty which interventions would work best for patients and under which conditions? We know that the share of all individuals who have used alcohol heavily is relatively high, but a much smaller share of that population develops AUD. Heavy drinking and binge drinking on their own, while still risky, are not the only problem. In a study published in Science, researchers took up this question: what leads only some individuals who drink heavily to drink compulsively? They tracked neuron activity in mice to gauge how experiences of punishment in the brain might affect compulsive drinking patterns.
What did this study find about brain areas and mice’s compulsive drinking?
This study found that relaying experiences of punishment makes mice less likely to drink compulsively. A circuit in the brain connects an area that processes punishment to the prefrontal cortex. The prefrontal cortex plays an important role in decision-making and evaluation of behavior. Previous studies have linked the prefrontal cortex to aspects of AUD. In this study, researchers identified activity in this circuit as a key factor in mice’s compulsive drinking patterns. They gave the mice sugar through tubes, and then gave them alcohol instead of sugar, referring to this as a “pre-binge” period. At this stage, the researchers used a technology called calcium imaging to observe the activity of neurons in the connecting circuit. The imaging allowed them to measure the effects of circuit activity on the mice’s drinking habits in the next stages of this study.
After their sugar-to-alcohol pre-binge, the mice were subjected to a binge period. In this stage, the mice could drink as much alcohol and/or water as they wanted, or no alcohol. Then, in a post-binge period, researchers gave the mice alcohol with quinine, an unpleasant mix. Three groups of mice emerged. Compulsive drinkers consumed large volumes of alcohol and continued to drink quinine. High drinkers had large volumes of alcohol but didn’t like the quinine. And low drinkers drank small volumes of alcohol. The imaging, conducted at pre-binge when mice first had alcohol, showed that the mice who went on to become compulsive drinkers had less activity in the connecting circuit, suggesting that limits in the circuit’s relay of punishment and aversion to decision-making function in the brain may contribute to the development of AUD. Researchers followed up by using technology to control neuron activity in the circuit. And when the researchers manipulated limited neuron activity in the circuit, the mice drank more. Manipulation enhancing the circuit’s activity led to less drinking.
Why is this important?
It’s possible that findings of neuron activity and drinking in mice won’t be borne out in studies of humans. The scientists who put this research on a top-10 list for 2019 might disagree, though. Yet when it comes to alcohol use, in particular, human experiences differ markedly from those of animals, simply because our brains and life experiences are so different. And it’s not clear exactly how alcohol affects this circuit in the human brain, or whether what counts as punishment to mice would also be punishing in humans, given our complicated considerations of risks and rewards in life. Researchers are starting to understand how drinking alcohol both reduces stress and anxiety in humans, and how it disrupts Central Nervous System (CNS) stress-responsive systems. It’s complicated. More than one brain system is involved, and, as a result, researchers have relied on medications that have multiple brain system targets. Until we develop a better understanding of the roles of stress, depression, sleep, anxiety and other conditions, AUD multi-target medications are expected to have greater efficacy than single-medication therapy.
But the results of this study are still very important. They are also intriguing because they suggest important roles for fear and punishment in promising new avenues for further research on AUD medications. If limited activity in this brain circuit, and diminished influence over how we make decisions after processing punishment and bad experiences, are a significant contribution to the development of AUD, then a medication adjusting or fine-tuning the circuit could be an important boost to patients. “With only three modestly effective drugs approved by the U.S. Food and Drug Administration to treat AUDs,” write experts Kimberly Nixon and Regina Mangieri in a review of the study, “this discovery is a needed leap forward—a newly-discovered circuit behind the essence of alcoholism in which to direct drug discovery efforts.”1
AUD is a top-ten leading risk factor for death and disability worldwide. A study observes, “Alcoholic liver disease, ranging from alcoholic fatty liver disease to advanced ALD (including alcoholic hepatitis, cirrhosis, and cirrhosis complications), is a leading cause of mortality in the United States, with nearly 250,000 deaths attributed to ALD” in one year.2 AUD is estimated to be around 6.2 percent of the population, much lower than the share of all adults who have consumed alcohol, though binge drinking is still common and risky. The mix of cultural, experimental, familial, peer-based, and genetic factors contributing to AUD is complex. And it’s been difficult to identify the genetic factors that increase the risk for harmful drinking. One study says, “Impaired GABA clearance within the amygdala contributes to alcohol addiction, appears to translate between species, and may offer targets for new pharmacotherapies for treating this disorder.”3 Craving for alcohol has been attributed to a different system, the opioid system. As an opioid receptor antagonist, Naltrexone likely works on the kappa opioid receptor to treat AUD.
It may be the case that AUD is a number of diseases, and that brain-pathway related diagnoses might be expected to predict pharmacological therapy selection and success. Depression often has different roles in AUD: it commonly co-occurs with the condition and often precedes it, and consistent binge drinking can also lead to depression. And when they occur together, they are harder to treat. Risk of suicide due to heavy alcohol use is common and well-documented.4 Suicide risk increase with alcohol use across all racial-ethnic groups, especially for younger males.5 Policies minimizing harmful alcohol use are essential for suicide prevention. Heavy alcohol use is estimated to result in 5.3 percent of all deaths worldwide. Moreover, this percentage is higher among the young — 13.5 percent of deaths among those between 20 and 39 years of age are attributable to alcohol.6 Death certificates suggest that alcohol-related mortality increased in the United States between 1999 and 2017. And since studies indicate that death certificates can understate the role of alcohol, it is likely involved in even more deaths than we understand officially at the moment. New findings confirm evidence of the public health costs of alcohol, and the need for improving surveillance of alcohol-involved mortality.7
That a Salk team of researchers have discovered a circuit in the mouse brain that might explain the gap between heavy drinking and compulsive drinking is very exciting. We also know where this brain pathway is — it runs between the prefrontal cortex and a region in the brainstem called the PAG. And we know that the PAG’s activity after first exposure to alcohol appears to predict future compulsive drinking. It may have future translational relevance in the study of AUD in people. As is almost always the case with substance use disorders, the most effective treatments are the targeted ones tailored to individual needs and interests, and we shouldn’t lose sight of that when reflecting on promising research findings that might help yield better medications over time. But we shouldn’t be overwhelmed by consistently troubling news about substance use issues, either, and it’s still appropriate to be excited about good results.
Nixon, K., Mangieri, R.A. (2019). Compelled to drink: Why some cannot stop. Science, 366(6468), 947-948. doi: 10.1126/science.aaz7357.
Wong, T., Dang, K., Ladhani, S., Singal, A.K., Wong, R.J. (2019). Prevalence of Alcoholic Fatty Liver Disease Among Adults in the United States, 2001-2016. JAMA, 321(17), 1723-1725. doi: 10.1001/jama.2019.2276
Augier, E., et al. (2018). A molecular mechanism for choosing alcohol over an alternative reward. Science, 360(6395), 1321-1326. doi: 10.1126/science.aao1157
Kaplan, M.S., et al. (2014). Use of Alcohol Before Suicide in the United States. Annals of Epidemiology, 24(8), 588–592, e2. doi: 10.1016/j.annepidem.2014.05.008
Caetano, R., et al. (2013). Acute Alcohol Intoxication and Suicide Among U.S. Ethnic/Racial Groups: Findings from the National Violent Death Reporting System. Alcoholism, Clinical and Experimental Research, 37(5), 839-846. doi: https://doi.org/10.1111/acer.12038
Hjemsæter, et al. (2019). Mortality, cause of death and risk factors in patients with alcohol use disorder alone or poly-substance use disorders: a 19-year prospective cohort study. BMC Psychiatry, 19(101). doi: https://doi.org/10.1186/s12888-019-2077-8.
White, A.M., Castle, I.P., Hingson, R.W., Powell, P.A. (2020). Using Death Certificates to Explore Changes in Alcohol-Related Mortality in the United States, 1999 to 2017. Alcohol Clin Exp Res, 44(1), 178-187. doi: 10.1111/acer.14239.
1. Siciliano, C.A., et al. (2019). A cortical-brainstem circuit predicts and governs compulsive alcohol drinking. Science. 366(6468):1008-1012. doi: 10.1126/science.aay1186. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/31754002
Dr. Mark S. Gold is a teacher of the year, translational researcher, author, mentor and inventor best known for his work on the brain systems underlying the effects of opiate drugs, cocaine and food. Read more by Dr. Gold here.