January 9, 2016

The holiday season is over, and in the words of Sean Connery, the damage is done. But aside from the myriad ways in which alcohol harms brain function, what most of us perhaps find more interesting is the question of alcohol’s effect on subjective experience. What events does alcohol consumption produce in the brain that might explain why this substance makes us feel the way it does – relaxed, numb to the senses, and uncoordinated? And where does the risk of becoming hooked come from?

Why does alcohol sedate, numb and make us uncoordinated?

The relaxing effect of alcohol is primarily underpinned by the fact that ethanol molecules interact with a class of so-called GABAA receptors – proteins which are embedded in the membranes of brain cells, or neurons

The power to suppress other neurons makes GABA-releasing cells fundamentally important in the workings of the brain. Since they are capable of precisely timing when other neurons can and cannot receive signals from various regions of the brain, many neuroscientists consider these cells the architects of neuronal communication (14).

This means that, as ethanol floats around and interacts with a neuron’s GABAA receptors, it both enhances the probability that these receptors will become activated and increases the period of time over which they will remain active (32). Ultimately, this produces more powerful suppression of the affected neuron.

The image below comes from an experiment in which researchers recorded from the membranes of mouse neurons while applying droplets of GABA combined with various doses of ethanol (1).

It’s clear that stimulating GABA receptors with the natural neurochemical has a negative influence on this neuron’s level of excitability (making it less likely to produce a signal). But quite importantly, we can see that this suppressive effect is boosted by alcohol, more so with increasing concentrations. While alcohol can’t activate GABAA receptors alone, we have solid evidence that it acts in concert with the brain’s own neurochemical to silence neurons more strongly than natural conditions permit.

The effects of alcohol are especially potent in the cerebellum – a region at the back of the brain which is particularly enriched in the GABAA receptor types that are maximally sensitive to ethanol (18).

We know that the cerebellum is critical for coordinating movements. Damage to this region makes individuals less able to control their eye movements, produce the complex tongue and lip movement sequences required for speech, regulate their posture, and correctly estimate the distance their limbs need to travel to reach objects (29). This is why cerebellar patients may have slurred speech, a strange manner of walking, and a tendency to slightly miss items they aim to grab with their hands. If any of these symptoms sound familiar to you, it’s because they also emerge when communication between neurons in the cerebellum becomes muffled when alcohol reaches the brain (10). This is why asking individuals to walk in a straight line or touch their nose is commonly used as a quick test of intoxication.

The key to understanding why alcohol also slows our reflexes lies with the spinal cord. This part of the nervous system generates most of our reflexes, from rapid withdrawal of the hand when we touch something hot or sharp, to the classic knee jerk reflex. When it comes to the effects of alcohol on reflexes, the culprits are receptors which are activated by glycine – the dominant inhibiting neurochemical of our spinal cord. We know that glycine receptors are essential for regulating the intensity of our reflexes, as individuals with genetic mutations which disturb these receptors tend to have highly exaggerated reflexes (12).

Perhaps more interesting is the fact that glycine receptors are also found in the brain (424), where alcohol causes them to produce some important psychological effects. In part, this occurs because glycine interferes with the dopamine neurochemical system, which might shed some light on why people can become hooked on alcohol. Importantly, it might also hold the key to future drug treatments for alcohol addiction.

Why do we crave alcohol? A story of dopamine and genes.

We know that dopamine is critical for inducing addiction and the desperation that comes with it to get a hold of more rewarding substance. When rats are given an opportunity to press a lever resulting in direct injections of cocaine into their own brains, they go on binges during which they press compulsively until they are exhausted. Such injections are known to immediately increase dopamine levels in the nucleus accumbens (NA) – a deep-brain cluster of cells which is a critical component of the brain’s reward system (30).That dopamine provokes cravings is widely accepted. It compels individuals to seek the thing which provided that dopamine spike in the first place, often regardless of whether they actually enjoy the thing they crave (7). Researchers have known for a while that ethanol consumption increases dopamine levels in the nucleus accumbens (819).

This was discovered when researchers observed that the massive dopamine release that occurred when rats were given alcohol was prevented by a drug which blocked glycine receptors. On the other hand, dripping glycine directly into the brain (which naturally stimulated these receptors) boosted the intoxicated dopamine burst. The fact that activating glycine receptors in the nucleus accumbens excited dopamine release seems a bit of a mystery, given what we know about glycine’s inhibiting effect on neurons. To understand roughly how researchers attempted to explain this somewhat surprising finding, let’s look inside the connections between neurons in the brain’s reward centres:

The importance of glycine receptors in this addictive chain of events has given rise to a new generation of potential drug treatments for alcoholism. Researchers recently found that treating alcohol-addicted rats with a drug that blocks glycine receptors reduced their preference for booze over water, as well as prevented drinking binges which tend to occur after a period of alcohol deprivation (20). Similar drugs have been found to reverse the worrying changes in activity of about a third of the genes known to be affected by chronic drinking (33). In the next few years, more research will reveal how we can harness our knowledge of the glycine system to tackle the problematic effects of alcohol

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