Mar 31, 2014

Announcer: Examining the latest research and telling you about the latest breakthroughs, the science and research show is on The Scope.

Host: As regretful spring breakers are recovering from their binge drinking escapades, it may be hard for them to appreciate that there is a positive side to the nausea, sleepiness, and stumbling. Dr. Sharif Taha, a professor of neurobiology and anatomy at the University of Utah, is lead author on a study that shows that there's a certain brain region that mediates learning from a bad hangover experience; an effect that could be important in keeping individuals from becoming problem drinkers in the future. Dr. Taha, what are some of the hallmarks of alcohol addiction?

Dr. Sharif Taha: So addiction I think of is just continued drug taking despite negative consequences. I think that's really what's at the core of addictive behaviors. And we study that specifically in the context of alcoholism. We study alcohol in our lab.

Host: So your work is involved in understanding who will become a problem drinker?

Dr. Sharif Taha: Addiction itself, obviously, there, you know, it's this multi-faceted thing. There's a lot going on in human addiction. And we can't study all of those many complicated facets in our rodent models, they are much simpler. So what we try to do instead, is we just try to look at a reduced set of behaviors that we think are relevant to subsets of human addictive behaviors.
One of the things we're very interested in is the transition from being a social drinker to becoming alcoholic. Right? What separates that small minority of people who do eventually develop these problems from other folks in terms of what's actually going on in brain circuits that controls that escalation of intake. That's really one of the things we'd like to understand.
And then another thing, another behavior that we'd like to understand that we talked about a little bit, is sort of further along in the timeline of addiction, or alcoholism. So people who are addicted to the drug, obviously they're aware of the negative consequences that are occurring because of this excessive intake, and they'd like to quit. Right? And they put a lot of effort into quitting, may be highly motivated. And there's lots of ways that you can try to do this. There's Alcoholics Anonymous, they have people go into rehab, but most of those efforts fail. Even after, even in very highly motivated individuals who can maintain abstinence for even years sometimes. So we'd like to understand the factors and signaling in the brain that underlies relapse to alcohol seeking after a period of abstinence.

Host: You're focused really on a specific part of the brain called the lateral habenula. Can you talk about what that is? And how it figures into alcohol [inaudible 00:02:40].

Dr. Sharif Taha: Sure. So yeah, the lateral habenula is a brain region that is fascinating, but it's perhaps best understood if I take a step back and talk about a different signaling molecule.
Most people know about dopamine. And they know that drugs of abuse actually cause dopamine to be released in the brain. And the dopamine is important in terms of the rewarding effects of drugs of abuse, and that's true of alcohol, that's true of other drugs of abuse as well.
We think that the lateral habenula is playing a role that's kind of complementary to the dopamine neurons. Instead of being important in terms of learning about the rewarding properties of drugs, it's important in learning about the aversive properties of drugs. So, this may be easiest to understand in terms of the basic, this experiment that we did. Do you want to transition to that?

Host: Yeah, let's hear about your research.

Dr. Sharif Taha: Yeah, so the basic finding that we have is that we can look at rats, or rodents, that are voluntarily consuming ethanol, and we use a paradigm in which we give them access to ethanol every other day, and a pretty potent ethanol solution, 20%. It's about as strong as gin. And if you give rats ethanol access in this schedule then they gradually escalate their intake over time. And eventually, they consume amounts that are quite substantial and they'll reach blood alcohol concentrations that exceed the 80 milligram percent. And so legally these would be drunk rats if they were driving.
And what we found is that if we compare intact rats to those in which we've inactivated the habenula, that these rats escalate their alcohol consumption much more rapidly, they do this over days, they escalate more rapidly than the intact rats. That's what separates a social drinker from someone who eventually becomes an alcoholic, is the fact that in the latter case they may start as someone who drinks socially. It's a glass or two of wine. But that becomes two or three, and three or four, and so on, and eventually they have a problem and their addicted.

Host: Okay. So let me just make sure I have this right. So the rats with an inactive lateral habenula drink more alcohol over time, and you think that might be significant because they may not feel the negative consequences of drinking.

Dr. Sharif Taha: That's right. So they escalate their drinking more rapidly than those control animals. And it's interesting, we don't know quite why that happens. It could be, our hypothesis is that it's one of two things, maybe a combination of both. It could be that as you said, they just don't experience the aversive consequences. Maybe the hangover is somehow not experienced as being quite as bad.
But we think that's less likely. We think instead what's happening is that they may experience something like a hangover effect, but they just can't learn from that hangover effect. So they can't associate that negative feeling they had with the taste of the alcohol that actually produced it. Right? And so, if you have some deficit in being able to associate that alcohol taste with negative consequence, the next time you get that alcohol taste you're likely to increase consumption.

Host: And so you actually did some experiments to address that very question. Right?

Dr. Sharif Taha: That's right. What we did in this experiment is we offered rats about 20 minutes access to a very sweet saccharin solution, but immediately after that what we did was we gave them some ethanol. We gave them a dose that was sufficient, that we know is sufficient to cause aversive effects. So the next time you give them the same sweet saccharin taste then their intake is reduced. Because they think now that this sweet taste is going to produce that negative outcome. Or, that visceral malaise. This is what happens in food poisoning. You taste something that you like, but then you become sick afterwards and you associate that taste you used to like with sickness so you avoid it thereafter. And that's exactly what's happening here.
So that's what happens in normal intact animals, but we can do exactly the same experiment in rats in which we inactivate the lateral habenula. And when we do that what we find is that when you give them access to that saccharin solution for the second time, then they don't show as much aversion. So it's as if they just haven't learned to associate that sweet taste with a negative outcome. And so, they don't show as much initial aversion and they also seem to recover from the aversion that they had more quickly. So they resume drinking the saccharin just after a couple of days, rather than having this aversion present for perhaps even a period of a week or so.
Obviously all kinds of different alcoholic beverages have their own taste and flavor components. And so voluntarily ingesting those can condition an aversion to all those tastes and flavors that you're experiencing. So that's why I feel like people move away from Jagermeister after college.

Host: Yeah, right.

Dr. Sharif Taha: It has a very distinctive taste and it's usually consumed to excess. And then, of course, as you said, right? If you've had a bad experience with that, then that taste is not something you want to experience any longer because you associate it with that bad outcome.

Host: Now that you have an idea of what neural circuit is involved in this, I mean, how can you use that to help people who might have problems?

Dr. Sharif Taha: We think this is particularly interesting and perhaps relevant to human alcoholism because there is a whole clinical literature that suggests that something similar may be going on in human drinking behaviors. And what they showed specifically was that those individuals that were least sensitive to the acute effects of alcohol, including the aversive effects, are the ones who eventually were at most risk to develop alcohol use disorders.
We think or results in the rodents are relevant to this result because what the human studies are telling us is that if you're less sensitive to alcohol's aversive effects, then you're likely to escalate your intake and become a problem drinker. And here what we have, what we think we have, is a brain circuit that controls specifically learning from the aversive effects of the drug. And we've made this, we've at least shown that this circuit is involved both in learning from aversive outcomes and then inactivating it also produces increases in intake. And so, these findings fit together in the way that we would expect. What we have to show now is that it's specifically an attenuation of learning from aversive effects that's driving this increased alcohol intake, and that's a link we haven't shown yet.
You can imagine that if we could actually understand the brain circuits that determine sensitivity to aversive effects of drugs, and determine, you know, may be involved in learning about these aversive effects. Then we might get a handle on at least vulnerability to developing, for instance, an alcohol use disorder, or becoming an alcoholic.

Announcer: Interesting. Informative. And all in the name of better health.

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