December 12

A Switch in the Brain for Compulsive Drinking

Most of us have drunk some form of alcohol in our lives. Many of us drink alcohol often. But we might know of only a few people who are pathologically addicted to alcohol. Are we, individually, differently prone to compulsive alcohol use? A recent paper, published in Science, attempts to answer this question using rodents. Simply, the answer to the question is yes. Individual-to-individual functional variations in the brain determine the vulnerability of someone getting compulsively addicted to alcohol.  

The authors started off with the intention of modelling excessive alcohol intake in rodents and studying their brains. Their primary goal was to be able to shed some light on how the brain changes in response to binge drinking. Compulsive alcohol drinking in humans can be defined as continued drinking in spite of negative health, social and economic consequences. The authors introduced a bitter tasting chemical with the alcohol to act as a negative consequence in their experiments with the rodents. They identified that there were individual-to-individual variations among the animals as some showed less sensitivity to the negative consequence than others. Some drank less even when the bitter taste was not added. Some dialed down their alcohol consumption while the bitter taste was added. And the third group of animals drank a lot anyway, irrespective of whether the bitter taste was added or not. This group of animals was considered to be compulsive drinkers. 

Now, is the brain of a compulsive drinker different from a light-drinker? In other words, do we have variable predispositions in our brain which determine the risk of alcohol addiction? Although the goal here is to attempt to solve the puzzles of the brain of a compulsive drinker, it is not necessary to study humans for that. In fact, many neuro-scientists prefer to study a non-human system to address many such questions, especially when they are investigating a particular problem at the molecular or neural levels. Non-human model systems (such as rodents) offer rigorous and controlled experimental set-ups and a sophisticated toolbox to study the genetic, molecular and pharmacological aspects of the problem. Scientists today know that many pathological drug-seeking compulsive behaviors are regulated by a region in the brain called medial prefrontal cortex (mPFC). Another region named peri-aqueductal gray (PAG) is known to be implicated in the response to aversive events, in general. These studies, which unveiled the roles of these brain regions in addiction-related pathologies, nonetheless, did not address the issue of individual-to-individual differences in the propensity to abuse drugs and how that could be reflected in the brain. The authors in this recent paper, while examining the responses of mPFC and PAG to excessive alcohol intake, found that these regions responded differently among animals when they were introduced to alcohol for the first time. These regions are more active in some animals than others in response to alcohol. The animals, in which these regions showed less activity in response to alcohol, generally became compulsive drinkers later in the tests. Hence, the authors could actually predict which animals would have a higher likelihood of becoming compulsive drinkers much before the animals actually started showing any behavioral signs. 

Kay Tye, Salk Institute, USA; one of the authors of the study (source: YouTube)

From the evidence of a correlation between the activity of certain brain regions in response to alcohol and the probability of an animal becoming compulsive drinker (less activity = more likely to be a compulsive drinker), one would predict that artificially decreasing the activity in these brain regions will lead to compulsive drinking. The authors used genetic engineering to test whether this prediction holds true. They engineered the animals in such a way that the relevant neurons (brain cells) became responsive to a certain wavelength of light (more on this technique). Upon exposure to this particular wavelength of light, these neurons could either be activated or inhibited. When mPFC-PAG was inhibited, the animals later became compulsive drinkers. The opposite exercise, namely the activation of the mPFC-PAG, made the animals drink much less. 

Nevertheless, one has to be cautious that it is only tested in animals and not in humans yet. It is very easy but probably equally risky to make oversimplified extrapolations of the findings of this study directly to humans. The light-induced genetic engineering, for example, by which they activated the brain cells, seems impractical at the moment to be translated to humans as a prevention therapy against becoming compulsive drinker. We still do not know of molecular markers associated with compulsive drinking. This study went as far as the level of neurons. It will be interesting to know whether there are specific molecular markers in these neurons which reflect whether one could potentially be a light-drinker or a compulsive drinker. These markers could then serve as therapeutic targets to tackle compulsive alcoholism. It will also probably be worth investigating whether individual-to-individual functional differences in the brain could also explain individual-to-individual differences in the likelihood of addiction to substances other than alcohol.