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The Central Nervous System

A Molecular Mechanism for Alcoholism?

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.

28 comments on “A Molecular Mechanism for Alcoholism?”

  1. Sharon Ishika Ghose says:

    Wonderful! I too hope that this will lead to more effective therapies. Personal reasons too. No longer sad. I drink. Measured. Never been drunk.

    1. Ram says:

      If the study is performed on inbred rats, assuming same genetic composition, how do you account for the genetic variation causing the low level of gab expression?

      1. D says:

        They say they used outbred rats

  2. Epic says:

    But bro it’s #dollarita day I’m not an alcoholic

  3. Anon says:

    Just curious if the GAT-3 level in certain individual can lower progressively with alchohol? Meaning your start with low expression and alcohol drives it even lower resulting in addiction? Can a mutated GAT-3 also bring about addiction?

  4. Isidore says:

    So if humans have similar biochemical vulnerabilities as rats (e.g. lower GAT-3 levels) what might a therapy look like?

    1. Scott says:

      Well, in theory, if a knock-out can cause/aggravate, then a knock-in could stop.

      But there’s an absolutely obscene amount of work to prove it.

  5. luysii says:

    Well maybe, but we ain’t rats. Therapies based on animal models of neurological and psychiatric disease have a terrible track record when tried in man.

    As a neurologist I was tasked with taking care of several physician alcoholics when they got in trouble. One of them did say, that he knew he’d be an alcoholic after just his first drink.

    So there may be something to this. Social factors are not to be ignored. Try driving through Gallup N. M. on a Saturday evening

    1. fajensen says:

      Well maybe, but we ain’t rats. Therapies based on animal models of neurological and psychiatric disease have a terrible track record when tried in man.

      OTOH – Deliberately creating addiction and addictive behaviours by applications which are all using patterns that was primarily derived from rat-models has been tremendously successful – at least for investors and some software companies. Breaking people is simpler and faster work than curing them!

      There used to be articles and seminars on “creating addictive technology” back when it was all a bit of innocent fun & games, now, it’s all gone under the radar after people are realising:

      a) how important a competitive advantage having these addictive technologies are, and,
      b) that the regulators are bound to bust up the app-party eventually and this happens sooner, if they have the documentation at hand, rather than them having to wait for the statistics to roll in.

      “Fortnite Battle Royale” is the latest and “greatest” game designed to suck all of the money and remaining life-force out of the teenagers. And it is working perfectly.

  6. TryingToBeRational says:

    My daughter is a recovering addict. I tried the Twain reasoning on her, “There are several good protections against temptation, but the surest is cowardice.” She said, somewhat more kindly, “Dad, you’re an idiot”. For some people, one drink, one pill, and that is it.

  7. Me says:

    ‘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.’

    My first thought re: this is would be easily explainable by alcohol-induced neuronal loss?

    1. Fuh Dge says:

      That’s an interesting thought. However, you’d need a localized mechanism of toxicity, because that decrease wasn’t seen in the other brain regions tested, yes?

      You’d think if it was non-specific tox. that there’d be global neuronal loss. If it’s on-target tox., there’s plenty of putative alcohol targets (GABAA, etc.) in those other brain regions, so I’m curious why the neuronal loss would be so specific.

    2. loupgarous says:

      Before graduating from college, I worked as a biomedical equipment technician at a regional state-owned hospital. We had a substance abuse wing (mostly EtOH abusers seen there) and I learned part of the standard care for new admits was a “banana bag” IV infusion of thiamine, folate, magnesium, and a multivitamins in either NS or D5W solution.

      The thiamine was to address Wernicke’s encephalopathy (thought to result from thiamine deficiency). A 2007 Lancet Neurology article, “Wernicke’s encephalopathy: new clinical settings and recent advances in diagnosis and management” lists several possible genetic causes of alcoholism associated with Wernicke’s encephalopathy, including variations in the GABA A receptor subunit gene cluster on chromosome 5q33, and mutations in gene coding for the high-affinity thiamine transporter protein SLC19A2.

      Some patients might be predisposed by these and other mutations or genetic variations toward alcohol dependence itself and early/prompt development of brain lesions associated with Wernicke’s syndrome. It might account for the “one-drink alcoholic” phenomenon.

  8. polymath says:

    luysii: “Therapies based on animal models of neurological and psychiatric disease have a terrible track record when tried in man.”

    That’s really what this study highlights. Therapies based on animal models have a terrible track record because, up until now and with the exception of a few outliers like Alexander et al’s Rat Park, the vast majority of experiments used environments where almost all the subjects are made to consume the drug at abusive levels. (Yeah the subjects have some kind of choice, but since Rat Park it was clear that most experiments used a forced choice.) Obviously those experiments would be unlikely to have external validity when applied to humans: for many “drugs of abuse,” including alcohol, many human users do not have catastrophic outcomes.

    There’s no guarantee that therapies based on this study will do better. Addiction, dependence, and abuse are terribly complicated, as one would expect just looking at the various words used to describe the outcomes we hope to avoid. But this is the most comprehensive study to address why some users might get addicted while others do not. Finally, finally, there might be something in the long and heavily-invested line of addiction research that is worth reading from a therapy or policy standpoint. Until now the field was basically useless to outsiders.

    (Which is not to say prior research in the field was useless, not at all, just that regardless of the press releases, prior research was really only useful to other researchers.)

  9. yuriwho says:

    Fascinating. I wonder what differentiates the people with AP (advanced placement) functional alcohol skills, (like Woodward) from those that are willing to drown themselves in misery. i.e. what neurochemical pathways temper the addiction allowing chronic functional abuse.

  10. Curious Wavefunction says:

    Indeed. Woodward and Churchill were both examples of outstanding functioning (high-functioning, in fact) addicts. It would be very interesting to find out what allows these people to stay unaffected even with decades of intense use.

    I’ll never forget what Churchill told FDR’s butler, Alonzo Fields, the first time he stayed in the White House:

    “Now, Fields, we had a lovely dinner last night, but we want to leave here as friends, right? So I need you to listen…I must have a tumbler of sherry in my room before breakfast, a couple of glasses of scotch and soda before lunch, and French champagne and ninety-year-old brandy before i go to sleep at night.”

    With that amount of alcohol coursing through him all day long, it’s a wonder Churchill managed to stay conscious, let alone make important war decisions.

    1. loupgarous says:

      Churchill’s free use of champagne was legendary, but assuming a snifter of brandy, two glasses of scotch and soda and a tumbler of sherry was the remainder of his intake…

      According to Ambrose Bierce, “In India one hundred thousand beef-eating and brandy-and-soda guzzling Britons hold in subjection two hundred and fifty million vegetarian abstainers of the same Aryan race.” Which makes you wonder what prodigies of warmaking the British could have been capable of had they remained entirely sober. Or not.

      1. luysii says:

        No, people can adapt to high levels of alcohol intake. I remember ER docs talking about the native american with a blood alcohol of 300 mgm% who ( 300 milligrams/deciliter) who appeared sober. They had the lab run it again to be sure.

      2. fajensen says:

        Thanks to Outsourcing –

        “The East India Company People (EIC) Management Manual” must have clearly stated that one shall never arm & assist the superior tribe because they might get ideas above their station, decide to kick your parasitic ass out of the place and get a better contract elsewhere. Instead, one shall pick ones new leadership amongst those third-rank wannabe tribes & troublemakers, that nobody else in the colony likes, so that the population will primarily gang up on their leadership and they therefore shall need continued EIC support to stay power.

        If no wannabes and troublemakers exist locally, then one shall import some and effect a “regime change”, handing power over to the newcomers, achieving the same objectives.

        The effects of the EIC are still very much with us today.

        1. loupgarous says:

          And, indeed, the “Great Rebellion”/”Sepoy Mutiny” ended the EIC for all intents and purposes in 1857, but the Government of India “rode the tiger”, hanging on for dear life, for almost a century afterward. Britain created a super state much, much larger than it was.

          My original point, I guess, was closer to luysii’s – drinking distilled ethanol was socialized among a large part of the British population by Churchill’s time. The effects of that overconsumption were recognized and people dealt with it (although Churchill suffered strokes from 1949 to 1963. I wonder what role Wernicke’s syndrome played in his overall clinical picture – ataxia is part of the characteristic “triad” of neurological symptoms).

  11. loupgarous says:

    Interesting. Early in my fight with paraganglioma (which preferentially attacks ganglia, hence the name) as well as DISH syndrome (which caused spinal nerve facet stenosis at several points), I experienced severe pain which required escalating doses of opioids. Not a satisfactory outcome.

    Then a physician placed me on very high dosage (3600 mg/day) of gabapentin, on the theory that my pain was at least partly neuropathy. Eventually (after PRRT, surgery, and both bland and chemo-embolization of inoperable tumors in the liver) I was able to taper my opioid agonist requirements from daily morphine to tramadol and high dose gabapentin with no noticeable opioid withdrawal symptoms. I welcome being able to focus better on intellectual tasks now.

    It may be significant, too, that tramadol has significant SSNRI activity.

  12. milkshake says:

    there must be GABA-related mechanism to alcoholism because gamma-hydroxybutyric acid fully substitutes for alcohol in alcoholics, and produces even more potent and pleasurable high that quite parallels the alcohol intoxication.

    1. Silverlakebodhisattva says:

      …and just out of curiosity, what does gamma-hydroxybutyric acid taste and smell like?

      1. drsnowboard says:

        you won’t remember…https://www.drugs.com/illicit/ghb.html

      2. Me says:

        If I were to guess: Sharp, a bit pungent with an edge of oil/butter that is ‘slightly off’ shall we say. I defer to anybody with direct experience, but that is certainly what that group of compounds smells like.

        1. myma says:

          Are you sure you are not describing grappa here?

    2. Dolph Dümpling says:

      Absolutely. And don’t forget about the poitive outcomes with baclofen therapy.

  13. A.Anonymous says:

    Great news, I hope this leads to real results in the clinic.

    Meanwhile, as a temporary fix, I have always applied the following rule to avoid being dragged into alcoholism if ever I were susceptible: Only drink when you are already happy, and never drink to get happy when you are not. This way you have an inbuilt negative feedback loop to ensure balance and moderation.

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