If this works out, it’s something that people have been trying to find for a long time: what exactly are the genetic/biochemical vulnerabilities that make a person susceptible to alcoholism? It’s long been suspected that there must be some, but untangling these things from sheer behavioral/environmental effects is extremely difficult.

It’s well known that rodents can learn to self-administer various drugs, but what I hadn’t known was that in most cases they’ll forgo that behavior if something more attractive is offered. For rats, that can be an intensely sweet solution (even saccharin), and almost all rats trained to self-administer alcohol will switch over to saccharin solution, never having encountered it before, if given the choice. But some rats (about 10-15% of the sample in this study) will apparently continue to self-administer alcohol in a way that seems impervious to alternatives, and this research team focused on those animals, to see if there was something different about them. The percentage of AP (alcohol-preferring) animals was the same, by the way, in a cohort that had already been exposed to the delights of self-administered saccharin.

These AP rats not only go for the alcohol in preference to another attractive choice – they’re willing to put up with a lot of negative stimuli to get it as well. “Higher aversive” concentrations of quinine weren’t enough – cue the gin-and-tonic jokes, but tonic water is about 80 ppm quinine, while these rats were willing to put up with 200mg/liter, which sounds highly aversive indeed and is a level that apparently sends any normal rat to the other side of the cage. When tested against water, the AP rodents wouldn’t touch the quinine solution – only when it had alcohol. And they were also willing to go across foot-shocking electric contacts to get the alcohol solution as well, which other rats quickly avoided by preference. Overall, the phenotype is uncomfortably close to behavior in human alcoholism.

A gene-expression screen in several brain regions of these animals showed the most changes in the amygdala, and of these, genes involved in GABA handling stood out for lower expression, especially the transporter GAT-3. This would allow GABA to accumulate in the amygdala, and indeed, this mechanism has been proposed as a possible factor in addictive behavior and anxiety disorders as well (the authors note that their AP animal also displayed anxiety-related behavior). But this paper goes further: they prepared an shRNA knockdown of the gene (AAV vector) and injected this into the amygdala of rats that had shown no alcohol preference – and as the GAT-3 protein levels decreased, the rats began to switch over to strongly preferring alcohol to saccharin. Finally, the team did a comparison of postmortem brain samples from human patients with and without alcohol dependence (corrected for age and other common factors) and found that GAT-3 levels were significantly lower in those with alcoholism.

Overall, this is pretty strong evidence (it seems to me) and it fits in with what we know about the disease. And this does indeed send it over into the disease category: philosophically, this is another reductionist chisel blow on the large stone edifice of traditional free will/rational choice/individual effort ideas about human behavior, which we all share to some extent. (Whether we’re comfortable about that or not, it won’t be the last one, either). It’s not clear if there are some people born with lower GAT-3 levels, or if they’re just more susceptible to having their GABA-handling system damaged by environmental factors (perhaps even by the process of drinking alcohol itself?) But this look like a solid lead to a better understanding of why – just as in rats – ten to fifteen percent of people who drink end up with real problems when they do so. My own guess is that there’s an innate deficiency in the GABA system in at least a good subset of severe alcoholics, based on reports from many people that from the first time they drank they felt an extraordinary change that they wanted to keep experiencing.

I very much hope that this can lead to more effective therapies, or even a screen to warn people that they may be in danger of alcoholism based on their amygdala activity. In case you’re wondering, I don’t drink, myself – not at all, and never have. But I still have personal reasons (warning: sadness) for wanting to see progress in this area, and I’m glad to see some being made.