Binge drinking, or the massive and rapid consumption of alcohol, affects the adolescent brain. Studies in humans and rodents reveal the mechanisms at play.
Alcohol consumption alters the brains of adolescents and young adults differently depending on whether the subjects are so-called “social” drinkers or fans of “binge drinking”.
Binge drinking is associated with damage to white matter (neuronal wiring) accompanied by alteration to the medium-term memory.
In rodents, it causes a long-term alteration of the function of one synaptic receptor essential for memory.
“The odd episode of binge drinking leaves no traces!” This statement, collected from secondary school pupils during visits to schools was the starting point for our research into binge drinking. The practice consists of drinking large quantities of alcohol in record time to get drunk. Popular with adolescents and young adults, this behaviour is not as harmless as they may [like to] believe. While all neurons are present at birth, the brain only finishes maturing at around 20-25 years, and remains especially vulnerable during this period. What specific damage does binge drinking cause compared to other methods of alcohol consumption? How many episodes are required to impair memory? How long does the learning ability remain affected? What are the cellular mechanisms in the neurons that are damaged during these episodes? To answer these questions, the international scientific community got together and launched a series of studies into binge drinking. Within this context, we formed the European project AlcoBinge, where we combined the approaches in humans and rodents. Our experiments in humans consisted of quantifying the damage to the brains of binge drinkers compared to so-called “social” drinkers. We also wanted to determine if binge drinking of alcohol led to notable modifications, different from those caused just by drinking alcohol. To identify the binge drinkers, we calculated a score that takes account of the speed of consumption and the frequency of the inebriations.
We believe that the dangers of binge drinking come not only from the quantity of alcohol absorbed, but also from the speed of ingestion, and hence the speed at which the spike in blood alcohol is reached. By measuring this score in 3 695 student drinkers who agreed to answer our questionnaire, we established that binge drinkers represented 40 % of the boys and 16 % of the girls in our sample. We then conducted MRIs (magnetic resonance imaging) on some of the subjects, divided into two groups: the binge drinkers and the “social drinkers”. We then analysed the condition of the white matter - the wiring through which nerve impulses flow – and the grey matter – the cell bodies of neurons which generate these nerve impulses. The results of the scans are striking. They reveal that binge drinkers have [more?] specific damage to their white matter compared to the social drinkers. The higher the binge score in boys, the more damage there is to the white matter (1). Worse still: this damage is associated with reduced performance in spatial memory tests. Our on-going analyses also indicate a greater loss of grey matter in the group of binge drinkers than in that of the social drinkers. Our results also reveal considerable differences between the boys and the girls. The hippocampus, the brain structure involved in encoding new memories and lessons, seems to be more affected in the girls.
Synapctic Plasticity altered
What are the cell mechanisms affected by alcohol when the brain is not yet mature? How exactly is memory altered? Before looking at the effects of binge drinking in adolescence, we studied an earlier stage of brain development in rodents: life in the womb. This enabled us to discover how alcohol very specifically impairs a cell property essential in the formation of memory and learning: synaptic plasticity. This function denotes the ability of synapses (*) to change the strength (or synaptic weight) of the link between two neurons, allowing them to rearrange themselves and create new brain circuits to encode new lessons learned. It is synaptic plasticity that enables us to record new information and thus learn. How? There are two essential mechanisms at play: “long-term potentiation” (LTP), corresponding to a sustained increase in synaptic response between two neurons, and “long-term depression” (LTD), corresponding to a sustained decrease in synaptic response. Both these mechanisms operate at level of the synapses. Usually, LTP occurs if the synapses on the excitatory neuron – the one that sends the information to the target neuron – releases a sufficient quantity of excitatory neurotransmitters, or glutamate molecules. These molecules then activate the target neuron by attaching to a specific membrane receptor: NMDA (N-Methyl-D-Aspartate). A stronger and more long-lasting connection then forms between these two neurons. Long-term depression involves the reverse process.
For the first time, we discovered that alcohol impairs LTD by targeting NMDA receptors. To prove this, we first evaluated the synaptic plasticity of neurons in the hippocampus of rats who had been exposed to alcohol in the womb. During gestation, we gave female rats a 10 % alcohol solution to drink (consumption equivalent to eight to ten glasses of alcohol per day in women). Then we measured the synaptic plasticity of their offspring when they reached adolescence, an essential stage in brain maturation. In practice, we recorded the electrical activity of neurons in sections of the hippocampus of these young rats to study the signals corresponding to LTP and LTD. It was already known that LTP was reduced in this animal model, but nothing was known about LTD, just as important in the encoding of learning. Our experiments revealed dysfunction in the LTD of these rats compared to the control rats that were not subjected to alcohol consumption in utero. It signalled an as yet unknown deficit in the cellular learning processes in these rats (2). Where does the dysfunction occur? At the NMDA receptor. In fact, by blocking this receptor using an inhibitory molecule, we noted that LTD became abnormal. More specifically, we successively blocked different protein subunits making up the structure of this NMDA receptor. Result: only one of them, the protein GluN2B, is responsible for the LTD anomaly. To confirm this, we measured the level of expression of this protein in sections of the hippocampus and noted a significant increase after in utero alcohol intake. This modification is significant as the presence of too much of this GluN2B subunit in the composition of the NMDA receptor affects its electrical properties and hence alters the synaptic plasticity signal. With behavioural analyses, we showed that this anomaly causes learning deficiencies and long-term memorisation in our rats.
What about binge drinking during adolescence? Does this mode of consumption target the same cell mechanisms? We showed that it does. To prove it, we exposed adolescent rats to just two binge drinking sessions, sufficiently far apart for the rats to return to zero alcohol levels before the second exposure. The advantage of this protocol is that it reproduces two episodes of drunkenness 24 hours apart with the levels of alcohol found in young people admitted to the emergency departments of hospitals following evenings of drinking. Thus, the level of alcohol in the blood of the rat reached two grams per litre. We then recorded the synaptic plasticity in sections of the hippocampus 24 and 48 hours after the two binge drinking sessions. We revealed that the harmful effects of binge drinking start 24 hours after the two drinking sessions. At this moment, we measured a decrease in LTD, which worryingly is entirely depleted after forty-eight hours (3). In other words, the animals had entirely lost one of the two main signals of synaptic plasticity involved in the encoding of learning. Additional studies revealed a disturbance in the function of the GluN2B subunit on the NMDA receptor, as with the intake of alcohol in utero. Monitoring our animals over time, we established that the absence of this LTD plasticity lasted for at least five days. Given that adolescence only lasts for two months in rodents with a life expectancy of about two years, this result would suggest that binge drinking has long-lasting harmful effects after only two episodes of alcohol intoxication. In order to demonstrate a link between these impaired cell mechanisms and learning ability, we completed the study by placing the animals in learning conditions involving LTD: analysis of new information. This test is based on the animal’s natural curiosity for its surroundings. It consists of familiarising an animal with two objects, A and B, by placing them within its enclosure. Once the animal is familiar with the objects, one of them is replaced with a new object, C and we measure the time spent by the animal exploring C. A healthy animal, familiar with objects A and B will spend more time exploring object C as it is unfamiliar. In other words, it is recognised as “new” (and A and B have been memorised). Those animals subjected to two binges and with no LTD did not spend enough time on C. This means that the absence of LTD impaired the learning of A and B, to such an extent that they could no longer consider C as new. In a final experiment, we reproduced the effects of two ethyl alcohol intoxications without using any alcohol. Instead we twice administered ketamine, which like alcohol, blocks the NMDA receptor, clearly demonstrating that alcohol impairs memory specifically by blocking this receptor. More worrying still, the rapid consumption of alcohol during adolescence seems to increase vulnerability to addiction in adulthood. We showed this by exposing rats to several episodes of binge drinking during their adolescence, i.e. once a day for two days (2 days “on”) interspersed with 2 alcohol-free days (2 days “off”) for a total of eight exposures. We then allowed them to grow to adulthood without exposing them to alcohol. In fact, we reproduced eight induction weekends for students – those famous days that are a pretext for binge drinking. Once adult, we submitted the animals to a series of behavioural tests to measure their reactions when exposed once again to alcohol. Result: the animals exposed to several episodes of binge drinking during adolescence, spontaneously consumed more alcohol as adults than their counterparts not exposed to binge drinking during adolescence. Even when given the choice of water, these rats preferred to drink alcohol. They also showed signs of anxiety greater than the control rats (4). This study reveals that consuming alcohol in the form of binge drinking during adolescence seems to leave “traces” in the brain that incite subjects to consume alcohol more readily as adults and furthermore, impairs mood control and makes them more anxious. We also observed that re-exposing the animals to alcohol is less effective in activating neurons in the nucleus accumbens, the structure involved in the pleasurable effects of alcohol. This suggests that these rats need to consume more alcohol to sufficiently stimulate this “pleasure centre”. A recent study in humans confirmed greater anxiety in adult women (but not men) who undertook binge drinking in adolescence.
5 to 7 glasses in two hours
The American National Institute on Alcohol Abuse and Alcoholism (NIAAA) defines “binge drinking” as a blood alcohol rate of 0.8 grams per litre within two hours, corresponding to around five to seven glasses. To represent this mode of consumption, a standard glass of any alcoholic drink (wine, spirit, beer, champagne, etc.) served in a bar contains 10 grams of pure ethanol which spreads to all the liquid compartments of the body, i.e. 60 % of our body mass (50 % in girls). However, glasses served at home or at private parties are often not “standard”. So, frequently some young people are consuming two or even three times these limits (ten to fifteen glasses [missing text?].
Greater risk of addiction
These data are alarming. They all point to the same conclusion: exposure to alcohol in the womb or in adolescence leads to considerable damage to learning ability with a common target in the neurons: the subunit GluN2B on the NMDA receptor. Contrary to what many young people say, binge drinking during adolescence leaves short-term and long-term traces. It makes people more vulnerable to alcohol addiction in adulthood and causes memory damage for far longer than the body takes to eliminate the alcohol from the system. Finally and to explore further, it seems essential that we understand the difference in sensitivity between boys and girls. This is all the more important as girls are catching up with boys in terms of the level and method of consumption, by increasingly adopting binge drinking.
(1) K.W. Smith et al., Addict Biol, doi: 10.1111/adb.12332, 2015.
(2) B. Silvestre de Ferron et al., Hippocampus. 25, 912, 2015.
(3) B. Silvestre de Ferron et al., Int J Neuropsychopharmacol, 6, 19(1), 2015.
(4) S. Alaux-Cantin et al., Neuropharmacology, 67, 521, 2013.
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University lecturer in neuropsychology, Fabien Gierski works in the Cognition Health and Socialisation Laboratory at Reims Champagne-Ardenne University. He is an expert in studying the factors of human vulnerability to addictive behaviours. His approach combines the techniques of cognitive and personality exploration with brain imaging. He is a member of the French network of alcoholism research.
Mickaël Naassila is a professor of physiology and has been researching alcohol addiction for twenty years. His expertise focuses on studying the neurobiological bases for addiction and searching for new treatments. He coordinated the European project AlcoBinge which aims at studying the impact of binge drinking on the brain. He is president of the French Society of Alcoholism and directs the French Network of Alcoholism Research.
Professor in neurosciences and having researched alcohol addiction for fifteen years, Olivier Pierrefiche is conducting work on rats to better understand the effects of alcohol on the electrical activity of neurons during brain maturation: from the womb to adolescence. He is a member of the board of the association SAF France, for the prevention of foetal alcohol syndrome.