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What can rats tell us about making better medications for alcohol use disorder?

July 25, 2019

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07252019_RYCU_RatsDespite causing significant morbidity, mortality, and consequences relative to many other substance use disorders, alcoholism remains understudied in key respects. Some research has discovered certain brain pathways and structures linked to incentive cycles and reward-seeking behavior, but these findings have not necessarily been translated into treatment improvements. We still really do not understand why so many people have had a drink or drink regularly and do not have problems, or specifically addressed why 15% of people who consume alcohol struggle with loss of control-compulsive alcohol use in their behavior. To better understand what might cause people to move from controlled to uncontrolled alcohol use, researchers at Linköping University, the University of Gothenburg, and the University of Texas studied the rates at which rats seemed to prefer to self-administer alcohol or the sweetener saccharin.

 

Alcoholic Behavior in Rats

Alcoholism is a “chronic relapsing disorder” that compels continued use despite high social, economic, and personal costs. This study sought to examine the extent to which rats would prefer alcohol over a “high-value alternative”—that is, foregoing a separately desirable activity, an important sign of substance use disorder—and whether those preferring alcohol display other behaviors consistent with those of substance use disorder. It also attempted to identify potential causes for compulsive alcohol-seeking behavior.

First, the researchers trained 32 rats to self-administer alcohol for 10 weeks. Self administration allows researchers to show that a drug of abuse stimulates its own taking and by definition has abuse and dependence liability. They then provided the trained rats with a daily choice between alcohol use and use of the non-caloric sweetener saccharin. Previous research had shown that only a small share of rats opted for compulsive, sustained use of alcohol over the high-value alternative of sweetener. Similarly, in this study, 4 of the 32 trained rats, or 12.5%, continued to prefer alcohol over sweetener — a rate the researchers describe as similar to that of humans. Because humans with substance use disorders have generally been in frequent contact with sugary things prior to the development of their substance use disorders, the researchers also gauged the effects of “pre-exposure” in preference, allowing another group of rats to drink water or sweetener for 4 weeks before introducing alcohol, but the authors found that prior exposure to sweet things had no effect. As researchers tested larger numbers of rats, 95 out of 620 rats (15.3%) persisted in their preference for alcohol over a prized alternative. This rate is again similar to that of human preference for alcohol. The researchers also noticed that alcohol-preferring rats did not simply value alcohol over saccharin, but also displayed increased motivation in their pursuit of it. Rats that prefer alcohol were not deterred from continued alcohol use, despite additional negative consequences such as the introduction of footshock punishments and quinine-adulterated alcohol.

 

Encouraging Results

As noted in the full study, there are critical gaps in our understanding of alcohol use disorder, and this research is an important step in assessing mechanisms by which individuals develop compulsive behaviors for alcohol instead of using it in a controlled fashion. My own work has questioned the assumed relevance of rat studies to the human experience and even suggested that we have developed great treatments for rats that don’t work to the same extent in humans. According to a Linköping University report, it is rare for the experiments on animals to align in results with related work on human alcohol use disorders. However, translational research may result in novel and effective treatment solutions for some. The university’s report explained that, on the basis of their work, the same research team is now collaborating with a company in the hopes of creating a GAT-3 (a type of GABA nuerotransmitter which plays an important part in regulating the nueral activity that relates to physiological and pahtological conditions) targeting medication for alcohol use disorder. This study also accords with the researchers’ previous work on GABA-relevance in alcoholism, presenting encouraging signs for anyone interested in developing a better understanding of the brain’s role in this substance use disorder — and in the most promising ways to constrain or alter that role.

 

References:

  1. Leifler, Karin Söderlund. (2018, June 25). A mechanism behind choosing alcohol over healthy rewards is found. Retrieved from https://liu.se/en/news-item/mekanism-bakom-varfor-vissa-valjer-alkohol-hittad
  2. Blum K, Gondré-Lewis M, Steinberg B, Elman L, Baron D, Modestino EJ, Badgaiyan RD, Gold MS. ( 2018) Our evolved unique pleasure circuit makes humans different from apes: Reconsideration of data derived from animal studies. J Syst Integr Neurosci.

Citation: Augier, Eric, Barbier, Estelle, Dulman, Russell, S., Licheri, Valentina, Augier, Gaelle, Domi, Esi, Barchiesi, Riccardo, Farris, Sean, Natt, Daniel, Mayfield, Dayne, R., Adermark, Louise, Heilig, Markus (2018, June). A molecular mechanism for choosing alcohol over an alternative reward. Science

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Mark Gold, MD

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.