Alcohol is a well-known ‘social lubricant’ used to produce disinhibition in social situations, but at the same time, excessive use produces the most harm to society of all drugs of abuse. The harmful use of alcohol is a global problem, which compromises both individual and social development. It results in 2.5 million deaths each year (source: World Health Organization).


People know that daily heavy drinking is associated with a high risk of alcohol dependence. There are countless studies from epidemiologists, clinicians and basic researchers showing that the amount of alcohol consumed daily is directly related with the development of alcohol dependence. This is a very simple equation. The more you drink, the more you become addicted.

If you agree with this conclusion, then there should be a very simple solution to limit the negative consequences of alcohol. Drink less! Many people understood that and instead of drinking everyday, they limit their consumption of alcohol to a couple of times a week, thinking that they are doing the right thing and “protecting” themselves from the risk of becoming an alcoholic.


The French Paradox

But is this really true? If you look at the data from the World Health Organization on alcohol drinking, you quickly realize that it is not that simple. Fig 1 shows the consumption of pure alcohol per year, the percentage of binge-drinking and the prevalence of dependence in 3 countries, France, USA and Canada.

The first thing you notice is that the French drink the most at 21 L/year. However, despite drinking the most, they have the lowest prevalence of alcohol dependence.

The second thing you notice is that the percentage of binge drinker is way more predictive of the prevalence of dependence than the total amount of alcohol consumed, suggesting that our simple explanation “The more you drink, the more you become addicted” is plain wrong. It is not the amount that matters it is the way you drink it, and binge drinking a couple of days a week might be worse than drinking daily. Obviously, these are just correlations and there are many other socio-cultural factors that may explain this paradoxical result.


Can rats binge drink?

So how do we solve this problem? How can we test whether limiting your consumption of alcohol for a few days a week puts you at risk or not?


That’s when basic neuroscience comes very handy. Rodents drink alcohol just like humans, so we took two groups of rats and tested how access to alcohol changes the way you drink. The first group had unlimited “24/7” access to alcohol for several months. The second group had access to alcohol only three days per week on Tuesday, Thursday and Friday. The rats were not forced to drink alcohol; they did so voluntarily as they also had access to water at the same time.


Drinking every few days leads to brain impairments

What happened? The rats with access to alcohol 24/7 drank the equivalent of a couple of glasses of wine a day and maintained a very stable daily intake for months. The second group with access only 3 times a week to alcohol rapidly escalated their alcohol intake to the point that they would drink 2-3 times more alcohol on a given day. They were “binge-drinking”, just like humans.


In tests conducted during “dry” intervals between drinking bouts, the binge drinking rats scored poorly on measures of working memory, an essential element of executive control. Tests of their brain tissue also revealed that during these withdrawal periods—when the animals would have been expected to be craving alcohol—the prefrontal cortex seemed relatively disconnected from the structures it is meant to regulate, such as the emotion-related amygdala.


We normally see such changes in the brains of humans or other animals that are highly dependent on alcohol, but here we found these changes in the rats after only a few months of intermittent alcohol use.

Remarkably, these impairments did not appear at all in the drink-every-day rats, whose alcohol intake remained stable. They just drink a bit like the French way, the equivalent of a couple of glasses of wine every day, and they’re fine; they don’t escalate.


As for the binge-drinking rats, their cognitive impairment went away if they were kept off alcohol for about two weeks—but the impairment would return if they simply drank again. One can see the vicious circle here. They drink to restore normal prefrontal function, but ultimately that leads to even greater impairment. This process would be of particular concern in adolescents and young adults, in whom the prefrontal cortex isn’t even fully developed.


Changes in the Brain

Further tests suggested that the immediate cause of the impairment in the binge-drinking rats was a small population of medial prefrontal cortex neurons known as GABA interneurons (Fig 2). These neurons are known to serve as “dimmer switches” for nearby excitatory neurons within the medial prefrontal cortex. In the binge-drinking rats, the GABA neurons were unusually active during periods of impairment. In general, the more active these GABA neurons are, the less the prefrontal cortex is able to do its primary job of exerting executive control over other, relatively impulse-driven brain regions.


We also found hints that the GABA interneurons in the binge-drinking rats may be activated by adjacent prefrontal neurons that secrete the stress neurotransmitter CRF. This molecule is already closely associated with alcoholism. In alcohol-dependent rats, and likely in human alcoholics, too, abstinence triggers a flood of CRF in the central nucleus of the amygdala—creating a feeling of anxiety that typically can only be alleviated by drinking again. Now we see that that this early dysregulation of the prefrontal cortex by binge drinking may also be driven by CRF.


We suspect that this very early adaptation of the brain to intermittent alcohol use helps drive the transition from ordinary social drinking to binge drinking and dependence.


Please visit Dr. George's website for more information on his work.

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