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Origins of Alcoholism

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  • Origins of Alcoholism

    A Landmark Study on the Origins of Alcoholism

    By studying rats in a smarter way, scientists are finally learning something useful about why some drinkers become addicted and others don’t.

    For Markus Heilig, the years of dead ends were starting to grate.

    A seasoned psychiatrist, Heilig joined the National Institutes of Health in 2004 with grand ambitions of finding new ways to treat addiction and alcoholism. “It was the age of the neuroscience revolution, and all this new tech gave us many ways of manipulating animal brains,” he recalls. By studying addictive behavior in laboratory rats and mice, he would pinpoint crucial genes, molecules, and brain regions that could be targeted to curtail the equivalent behaviors in people.

    It wasn’t to be. The insights from rodent studies repeatedly proved to be irrelevant. Many researchers and pharmaceutical companies became disillusioned. “We cured alcoholism in every rat we ever tried,” says Heilig, who is now at Linköping University in Sweden. “And at the end of every paper, we wrote: This will lead to an exciting treatment. But everything we took from these animal models to the clinic failed. We needed to go back to the drawing board.”

    Heilig doesn’t buy that mice and rats have nothing to teach us about addiction. It’s more that researchers have been studying them in the wrong way.
    Those alcohol-preferring rats showed other hallmarks of human addiction, too. They spend more effort to get a sip of alcohol than their sugar-preferring peers, and they kept on drinking even when their booze supply was spiked with an intensely bitter chemical or paired with an electric shock. “That was striking to me, as a clinician,” says Heilig. “Embedded in the criteria for diagnosing alcoholism is that people continue to take drugs despite good knowledge of the fact that it will harm or kill them.”

    Many lab studies treat animals as if they were identical, and any variation in their behavior is just unhelpful noise. But in Augier’s work, the variation is the important bit. It’s what points to the interesting underlying biology. “This is a really good study,” says Michael Taffe, a neuroscientist at the Scripps Research Institute who studies drug addiction. “Since only a minority of humans experience a transition to addiction, [an approach] such as this is most likely to identify the specific genetic variants that convey risk.”
    The amygdala is an almond-shaped region that sits deep within the brain, and is heavily involved in processing emotions. When Augier looked at the amygdala of alcoholic rats, he found signs of unusually low activity in several genes, all of which are linked to a chemical called GABA.

    GABA is a molecular red light: Certain neurons make and release it to stop their neighbors from firing. Once that’s done, the GABA-making neurons use an enzyme called GAT3 to pump the molecule back into themselves, so they can reuse it. But in the amygdala of alcohol-preferring rats, the gene that makes GAT3 is much less active, and makes just half the usual levels of the pump. GABA accumulates around the neighboring neurons, making them abnormally inactive.

    The consequences of this are unclear, but Heilig thinks that all this extra GABA hampers the rats’ ability to deal with fear and stress. They are naturally more anxious, which might explain their vulnerability to alcohol. He predicts it will take another five years of work to fully close this loop. But for now, his team have definitely shown that GAT3—the GABA-recycling pump—is important. They took rats that prefer sugar and deliberately reduced the levels of GAT3 in their amygdala. This simple procedure was enough to convert those resilient rodents into addiction-prone, alcohol-preferring 15-percenters.

    At this point, the team submitted their result to a journal, which agreed to publish them. Good news—but after Heilig’s long history with rat-shaped dead-ends, he wanted to do one more experiment. “Curing alcoholism in rats is not important,” he says. “What’s important is what this looks like in humans with alcohol addiction.”

    As it happens, it looks much the same. Heilig’s colleagues examined postmortem tissue samples from people who had donated their brains to research, some of whom had alcohol addiction. As in the rats, they found nothing unusual in five of six brain regions. But in the amygdala, they found low levels of GAT3.

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