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Graeme F. Mason, Ph.D.
Professor of Diagnostic Radiology and Psychiatry
Director of Metabolic Modeling; Psychiatric MRS, and Neuroimaging Sciences Training Program
Yale University School of Medicine
Dana Grantee: 2005-2010
You are studying genetic vulnerability to alcohol dependence and have recently completed a small study using Magnetic Resonance Spectroscopy (MRS) to evaluate alcohol-induced changes in the concentration of certain neurotransmitters. What have you found so far?
Graeme F. Mason: We set out to see if people with a family history of alcohol dependence and people with a known genetic vulnerability to alcohol dependence (the GABRA2 receptor gene) would react less, neurochemically, to alcohol intake than those without the genetic vulnerability. We don’t have that answer yet because we need more subjects to have a really effective comparison of people who are family history positive vs. negative. But we did see a very rapid effect of alcohol on levels of the inhibitory neurotransmitter GABA: its concentration dropped within a few minutes of alcohol intake, before the alcohol even reached the level of legal impairment.
What do these measurements tell us about how alcohol affects the brain?
Everything the brain does is mediated by chemistry. Nerve cells use neurotransmitters–brain chemicals–to communicate with one another. The most common one is glutamate, which is an excitatory neurotransmitter: it stimulates other neurons to fire. GABA is closely related chemically to glutamate, but in the adult brain it partially inhibits nerve cells from acting.
Certain drugs, such as valium, act on the sites that are targeted by GABA: they make GABA more potent so it inhibits nerve activity more effectively. Alcohol also binds to GABA receptors, including the GABRA2 type, making it function more efficiently. If you’ve got alcohol in your system, every molecule of GABA that’s released is more effective at inhibiting neurons. So as you drink, GABA is slowing down nerve activity and your brain doesn’t function as effectively.
Did you find effects on neurotransmitters other than GABA?
We also measured glutamate. While the changes in glutamate concentration didn’t reach statistical significance in this first study, it looked like glutamate decreased gradually over the period of alcohol administration. It was a slow decline and the levels bounced around a bit, but the overall trend was down. Nobody knows yet what it means when glutamate levels go down, but it looks like alcohol has that effect.
Some interplay with glutamate was expected. You can think of the neurotransmitter systems in the brain like a bowl of jello. If you put a jello mold on a plate, and you poke one side of it, the whole thing wiggles. GABA, glutamate…all of these neurotransmitter systems are interconnected, and the brain regions they act in are interconnected. Alcohol affects glutamate receptors, dopamine receptors, and so on.
How does this fit with other research about alcohol dependence?
The genetic story of GABRA2 is a big theory in vulnerability to dependence right now, with data to back it. In practical terms, we all know people who feel tipsy after half a glass of wine and others who can drink a lot and still not feel tipsy. Some of that response is related to differences in how the liver metabolizes alcohol, but other people feel the positive effects of alcohol with less apparent impairment.
Others have studied this phenomenon by looking at body sway in people who are under the influence of alcohol. They’ve found that people with a family history of alcohol dependence don’t sway as much as people without a family history; they’re less impaired by the alcohol and able to consume more. It’s as if they don’t get the same signals telling them: ‘I’m getting tipsy; I’d better stop.’
What does this research tell us about gene-brain-behavior interactions?
Well, alcohol is a pretty dirty drug–it affects a lot of things in the body and in the brain. With regard to the GABA receptor, we know that one form of the gene that makes the receptor (GABRA2) is associated with risk for alcohol dependence. We know that alcohol normally enhances GABA inhibition–essentially slowing down nerve cell firing–but if you have the risk-conferring form of the GABRA2 gene, alcohol’s enhancement of GABA is tamped down. Since GABA is an inhibitory neurotransmitter, nerve cell firing is less inhibited.
In short, alcohol is less likely to impair brain activity in people with the vulnerable form of the gene than it is in people without it. This could explain the findings that body sway is less in people with a family history of alcohol dependence.
Now, that doesn’t mean that people who feel less impaired should drive a car, for example, because alcohol has many other effects in the body and brain. They’re still going to have impaired judgment, and they’re still going to have a slower reaction time, even if they may be a little less impaired than somebody who doesn’t have that gene. The problem is that they’re not going to feel impaired.
What do you see as the practical implications of this research so far?
It’s funny, because we performed all this complicated scanning and chemistry but the coolest thing about this study for me were the responses to a simple question we asked participants: how many drinks do you feel like you’ve had?
We asked the question at the beginning of the study, during the infusion, and throughout the study. At the beginning, when nobody had consumed any alcohol, they all said zero drinks. As we ramped up their alcohol intake, the number of drinks they felt like they’d had also increased reaching a maximum at about the time blood alcohol levels plateaued (20-30 minutes, on average). As time passed, they felt like they’d had less and less to drink, even though their blood alcohol level stayed constant. The person who felt the most intoxicated at the plateau actually felt like he’d had nothing to drink by the end of the experiment, even though his blood alcohol remained elevated.
This result wasn’t surprising to a lot of people in the alcohol field but it really had an impact on my view. I used to think that people who got in cars and drove drunk were just thoughtless jerks–-and some of them probably are. But I would bet that a lot of people come out of a bar thinking they’re sober when they’re not. These data tell me that people are poor judges of how inebriated they still may be, especially when blood alcohol has remained stable for a while or even if it is falling.
What are your next steps in this line of research?
Coming back to neurochemistry and genetics, one thing I want to know is: are the people with genetic vulnerability going to have to drink more to feel like they’ve had the same amount of alcohol as those without the gene? I predict they will, and that they will show less of a change in probably all of the chemicals we measured at a given level of alcohol.
I also want to know what impact other drugs–like naltrexone, which has been effective in some populations for treating alcoholism–have on these measures in people who have the genetic vulnerability vs. people who don’t. We know many drugs interact with GABA as well as other neurotransmitter systems, like the opiate system in the case naltrexone. It would be great if we could identify the populations where a given anti-alcohol treatment can be effective vs. ones in which it is not likely to be.
There’s been a lot of talk about “personalized medicine” via pharmacogenomics, but not a lot of practical applications of it. How realistic is it for brain disorders like alcohol addiction?
Medicine overall is headed toward this kind of individualized therapy. We’re beginning to even see a little of it find its way into clinical practice. The brain is a difficult system to do this in because of the interactions of all the neurotransmitter systems, and because we understand so little about how they interact. It’s often presented as a seesaw effect but it’s not that simple. There is an almost infinite capacity for subtle regulation because of the different types of receptors and the different subunits within each type.
Still, the lure of individualized medicine is huge. Rather than waste weeks or months trying to figure out which drug and which dose is right for each individual, we could look at their genetics and tailor their treatment accordingly. I’m not proposing that every person seeking treatment should be scanned to see which medicine they should use. I want to use this research to understand the neurochemistry so we can then take a blood sample, do the genetics, and be able to say: ‘This is what’s going on in your brain, and this is the medicine that’s likely to work best for you.’