The link between alcohol and anxiety

Alcohol use and anxiety often overlap in individuals, and many people report drinking to ease their anxiety. While speculations exist, it is unclear if anxiety is a reason that many individuals drink or the result of drinking. Untangling this relationship in humans is tricky, so we turned to animal models. There is a key feature in animal models that is advantageous when trying to determine the relationship between alcohol abuse and anxiety: we have full control over when the animals receive their first exposure to alcohol. This gives us the ability to determine if anxiety-like behaviors predispose animals to alcohol use and allows us to determine the underlying brain mechanisms. 

How do we gauge anxiety in a mouse?

In mice, because we can’t ask them if they are feeling anxious, we use tasks like the elevated-zero maze to determine “anxiety-like” behavior. In this task, the mice are given the opportunity to stay in the enclosed, dark areas of the maze or explore the open, “risky” areas of the maze. The more risk-avoidance, or time spent confined to the dark, enclosed parts of the maze, the more “anxiety-like” behavior the animal is displaying. When given alcohol, mice increase the amount of time they spend on the open arms of the elevated zero maze, indicating the anxiolytic (anxiety-busting) effects of alcohol.

Like humans, mice show varied responses to alcohol

Mice are a shockingly good substitute for humans when studying alcohol use disorder. One reason for this is that, like humans, mice show a variety of responses to alcohol. Despite examining an inbred and genetically identical group of wildtype mice, some mice show increased time in the risky zones of the elevated zero maze following alcohol, while others don’t. This indicates that some of the mice were more sensitive to the anxiolytic effects of alcohol than others. We also found that the mice that are more sensitive to the anxiolytic effects of alcohol consume more alcohol when give access to drink voluntarily. We are very interested in understanding what drives this individual variability, because it might help us understand why some people are more prone to developing damaging alcohol consumption, while others aren’t. 

Increased risk-avoidance at baseline is associated with a potent anxiolytic response to alcohol

In this study, we determined that mice showing higher risk-avoidance behavior at baseline were more sensitive to the anxiolytic potency of alcohol. This suggests that a pre-existing “anxiety-like” state is associated with higher relief when alcohol is introduced, and higher consumption when give access to drink voluntarily.

What neurological factors in risk-averse mice might drive their higher sensitivity and preference for alcohol?

To better determine the underlying brain mechanisms, we turned our focus to the striatum, a brain region known to play an important role in the rewarding and reinforcing properties of drugs of abuse, including alcohol. Using in vivo approaches, we demonstrated that activation of a specific subpopulation of neurons, containing the dopamine D1 receptor, in the dorsal aspect of the striatum is required for the anxiolytic effects of alcohol. We also found that the same group of neurons is activated both during exploration of the open, “risky” areas of the elevated zero maze and when alcohol is administered. 

Dopamine D1 receptors play a role in sensitivity to the anxiolytic effects of alcohol

Together, these findings indicate that dopamine D1 receptor containing neurons could be central to the varying responses to alcohol seen in our wildtype mice. We hypothesized that the dopamine D1 receptor itself might be playing an important role. To test this, we assessed the degree of alcohol relief in many mice and then we extracted the striatum and determined the levels of dopamine D1 receptor mRNA. To our surprise, we found that there was no correlation between dopamine D1 receptor mRNA and anxiolytic sensitivity to alcohol. 

Stumped, we turned our attention to another dopamine receptor that has been shown to play a central role in addition: the dopamine D2 receptor. However, just like dopamine D1 receptor mRNA, there was no correlation between the dopamine D2 receptor mRNA and the anxiolytic sensitivity to alcohol. Clearly more confused than before, we looked at the ratio of the dopamine D1 receptor mRNA to dopamine D2 receptor mRNA. Voila! The ratio of dopamine D1 to D2 receptor mRNA levels correlated with the anxiolytic sensitivity to alcohol, and the propensity to drink alcohol when given the opportunity. In other words, mice with higher dopamine D1 to D2 receptor mRNA levels in the dorsal striatum were more sensitive to the anxiolytic effects of alcohol AND more willing to consume it!

The ratio of dopamine D1 to D2 receptors is the best predictor of sensitivity to the anxiolytic effects of alcohol and the likelihood to consume alcohol despite adverse outcomes

With this newfound knowledge that the ratio of dopamine D1 to D2 receptors is important in dictating the sensitivity to alcohol’s anxiolytic effects, we generated a mouse with a high ratio of dopamine D1 to D2 receptors. We found that by manipulating the ratio of receptor expression, we generated mice that are more risk-avoidant at baseline and show stronger relief from “anxiety-like” behaviors when administered alcohol. Finally, these mice were willing to consume alcohol, even when we tainted it with a bitter flavor, while mice with normal dopamine D1 to D2 receptor ratios were no longer willing to consume it. This indicates a willingness to consume alcohol, despite negative consequences.

Conclusions

Taken together, our results indicate that a risk-avoidant phenotype is associated with greater relief by alcohol and a stronger preference for drinking. We also found a causal link between these factors, indicating that an “anxiety-like” state promotes increased alcohol relief and drinking despite negative consequences. We speculate that repeated alcohol use may further intensify the preexisting “anxiety-like” state, particularly during withdrawal, potentially leading to a worsening clinical cycle. These findings have significant implications for the therapeutic treatment of alcohol use disorder and anxiety.

Further, we identify the balance between striatal dopamine D1 and D2 receptors as a key regulator of risk-avoidance and alcohol response in mice. Mice with elevated dopamine D1 to D2 receptor binding display a predisposition towards risk-avoidance and show more relief from “anxiety-like” behaviors with alcohol, even on first exposure. Over time, repeated alcohol exposure led to a higher propensity for punishment-resistant drinking. Our expanding understanding of the neuronal mechanisms underlying alcohol use and anxiety could support the future development of assays screening for those at risk of developing alcohol use disorder, as well as aid in the development of targeted pharmaceutical treatments for anxiety and alcohol use disorder.