Eric Augier, who recently joined Heilig’s team, tried a different approach—one pioneered in his former laboratory to study cocaine addiction. After training rats to self-administer alcohol, he offered them some sugary water, too. This better mimics real life, in which drugs exist simultaneously with other pleasurable substances. Given a choice between booze and nectar, most rats chose the latter. But not all of them: Of the 32 rats that Augier first tested, four ignored the sugar and kept on shooting themselves up with alcohol.
“Four rats is laughable,” says Heilig, referring to the study’s small size, “but 620 rats later, no one’s laughing.” Augier repeated the experiment with more rats of various breeds, and always got the same results. Consistently, 15 percent of them choose alcohol over sugar—the same number as the proportion of human drinkers who progress to alcoholism.
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.”
That is exactly what the team did next. They compared the alcohol-preferring and sugar-preferring rats and looked for differences in the genes that were active in their brains. They focused on six regions that are thought to be involved in addiction, and found no differences in five. “But in the sixth, we did,” says Heilig. “And it made me smile because I started out doing my Ph.D. on the amygdala.”
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.