A lesser known mechanism for alcohol tolerance

People who drink a lot of alcohol have a high alcohol tolerance. By this, I mean two things:

1. They can drink a lot of alcohol and still have a relatively low blood alcohol level.

2. They can have a high blood alcohol level and still be relatively functional.

There are two traditional explanations for this. For the first, the traditional explanation is that alcoholics have an enlarged liver, better able to handle large amounts of alcohol than a normal liver. For the second, the traditional explanation is that alcoholics can “handle their alcohol” better, meaning that they are better psychologically adapted to the effects of alcohol.

These explanations are correct, but they aren’t the whole story. Blood alcohol levels of above 0.4% are often fatal to a normal person, and are at least liable to put the person in a coma. And yet some alcoholics can have blood alcohol levels of 1% or higher and still be functional enough to drive a car.

This can’t be explained by an enlarged liver. The liver can slowly metabolize alcohol from the bloodstream, but, if your blood alcohol level is already that high, it’s too late. And there’s no way to “handle” being in an alcohol-induced coma.

There has to be a cellular adaptation, presumably one that affects the brain. And this adaptation seems to be a modification of the big potassium (BK) channel, which in turn has direct effects on the parts of the brain that are affected by alcohol.

Let’s go through a quick refresher of what the BK channel is, and then discuss the evidence for this. 

The BK channel is a ubiquitous voltage-gated potassium channel. As its name suggests, it’s big: it can allow for a large amount of potassium ions to cross the cell membrane. This is broadly useful. When calcium or magnesium ions bind to the receptor site (or when there’s a large voltage), potassium ions can rush into the cell. This slow buildup then sudden release is useful in action potentials, muscle contraction, and many other bodily functions, as it turns what would be a gradient of potential into a binary with a threshold value.

The threshold value of the BK channel is not a set value, but can instead be modified. It’s modified by auxiliary proteins which change the shape of the channel and its sensors, making it more or less sensitive to different sorts of ions. 

Alcohol induces the opening of BK channels, or, to be more precise, makes openings longer and closures shorter. So, whatever conduction is going to happen is made more likely by alcohol. However, if the BK channel is modified with β4-subunits, the BK channel can be made more resistant to the effects of alcohol.

This modification seems to be part of the long-term development of tolerance. Exposure to alcohol upregulates microRNA (mir-9), which in turn modifies BK mRNA, selectively destabilizing certain types of BK mRNA.

So what does all this have to do with why alcoholics don’t end up in comas with >1% BAC?

Well, part of it comes down to the NMDA receptor. The NMDA receptor is one of the main neuroreceptors in the brain, responsible for connecting the brain to the body. NMDA receptor antagonism results in dissociation. Ketamine, for instance, is a potent NMDA receptor antagonist, which is why it’s used as an anaesthetic. It makes people dissociate from their bodies so surgeons can work on them.

Alcohol is also an NMDA receptor antagonist, which is why people who drink a lot of alcohol can slip into a coma. And guess what forms complexes with NMDA receptors? BK channels. Long-term alcohol use can therefore presumably modify the BK channels that are complexed with NMDA receptors, making it more difficult for alcohol to antagonize them even at high BAC levels.

The consequence of this would then be that the development of alcohol tolerance could be slowed or halted by preventing the modification of BK channels, like by using RNAi to degrade certain types of BK mRNA. 

It’d also be interesting to explore whether this mechanism is at play in other types of drug tolerance, like opiate tolerance, in order to examine if RNAi could be used there as well.