A Brain Region for Resisting Alcohol’s Allure

As recovering spring breakers are regretting binge drinking escapades, it may be hard for them to appreciate that there is a positive side to the nausea, sleepiness, and stumbling. University of Utah neuroscientists report that when a region of the brain called the lateral habenula is chronically inactivated in rats, they repeatedly drink to excess and are less able to learn from the experience. The study, published online in PLOS ONE on April 2, has implications for understanding behaviors that drive alcohol addiction.

While complex societal pressures contribute to alcoholism, physiological factors are also to blame. Alcohol is a drug of abuse, earning its status because it tickles the reward system in the brain, triggering the release of feel-good neurotransmitters. The dreaded outcomes of overindulging serve the beneficial purpose of countering the pull of temptation, but little is understood about how those mechanisms are controlled.

U of U professor of neurobiology and anatomy Sharif Taha, Ph.D., and colleagues, tipped the balance that reigns in addictive behaviors by inactivating in rats a brain region called the lateral habenula. When the rats were given intermittent access to a solution of 20% alcohol over several weeks, they escalated their alcohol drinking more rapidly, and drank more heavily than control rats.

“In people, escalation of intake is what eventually separates a social drinker from someone who becomes an alcoholic,” said Taha. “These rats drink amounts that are quite substantial. Legally they would be drunk if they were driving.”

The lateral habenula is activated by bad experiences, suggesting that without this region the rats may drink more because they fail to learn from the negative outcomes of overindulging. The investigators tested the idea by giving the rats a desirable, sweet juice then injecting them with a dose of alcohol large enough to cause negative effects.

“It’s the same kind of learning that mediates your response in food poisoning. You taste something and then you get sick, and then of course you avoid that food in future meals,” explained Taha.

Yet rats with an inactivated lateral habenula sought out the juice more than control animals, even though it meant a repeat of the bad experience.

“The way I look at it is the rewarding effects of drinking alcohol compete with the aversive effects,” explained Andrew Haack, who is co-first author on the study with Chandni Sheth, both neuroscience graduate students. “When you take the aversive effects away, which is what we did when we inactivated the lateral habenula, the rewarding effects gain more purchase, and so it drives up drinking behavior.”

The group’s findings may help explain results from previous clinical investigations demonstrating that men who were less sensitive to the negative effects of alcohol drank more heavily, and were more likely to become problem drinkers later in life.

The researches think the lateral habenula likely works in one of two ways. The region may regulate how badly an individual feels after over-drinking. Alternatively, it may control how well an individual learns from their bad experience. Future work will resolve between the two.

“If we can understand the brain circuits that control sensitivity to alcohol’s aversive effects, then we can start to get a handle on who may become a problem drinker,” said Taha.

Alcoholic fly larvae need fix for learning

Fly larvae fed on alcohol-spiked food for a period of days grow dependent on those spirits for learning. The findings, reported in Current Biology, a Cell Press publication, on November 29th, show how overuse of alcohol can produce lasting changes in the brain, even after alcohol abuse stops.

The report also provides evidence that the very human experience of alcoholism can be explored in part with studies conducted in fruit flies and other animals, the researchers say.

"Our evidence supports the long-ago proposed idea that functional ethanol tolerance is produced by adaptations that counter the effects of ethanol, and that these adaptations help the nervous system function more normally when ethanol is present," says Brooks Robinson of The University of Texas at Austin. "However, when ethanol is withheld, the adaptations persist to give the nervous system abnormal properties that manifest themselves as symptoms of withdrawal."

Robinson and his colleagues found that alcohol consumption, at a level equivalent to mild intoxication in humans, at first impeded learning by fly larvae. More specifically, those larvae had some trouble in associating an unpleasant heat pulse with an otherwise attractive odor in comparison to larvae that had not been drinking alcohol.

After a six-day drinking binge, however, those larvae adapted and could learn as well as normal larvae could. In fact, the alcohol-adapted animals learned poorly when their ethanol was taken away from them. And, when given alcohol back, their learning deficit was erased.

Robinson says that the findings are the first proof of cognitive ethanol dependence in an invertebrate, suggesting that some of ethanol’s ability to change behavior must begin at the cellular level. After all, flies and humans share many of the same features at the level of individual neurons, and not so much in terms of the way those neurons are put together into working circuits.