The two mice are the same amount of drunk, which is to say, a lot.
Both are wobbly on their little legs, and both are moving slower than normal. But while one is feeling so sauced that it can’t turn itself over when a lab technician puts it on its back, the other is scurrying around the lab table — inhibitions gone — and nearly runs right off the edge before a gloved hand saves its life.
Now imagine them as high school students who hit a frat party and try alcohol for the first time.
The first mouse is the guy who has half a beer, thinks it tastes bad, and is slumped on the couch. And the second guy? He’s the one dancing on a table after chugging three beers.
“Who do you think is going to have a problem later in life?” asks Dr. Richard Radcliffe, a professor at the Skaggs School of Pharmacy on the University of Colorado Anschutz Medical Campus.
The mice are his, and what Radcliffe is trying to figure out is why some people are more sensitive to alcohol than others — and why some really like to drink. Radcliffe’s lab is among several across the world focused on figuring out how genetics predisposes people to alcoholism, work that could lead to better medications and psychotherapy for people who are addicted to alcohol.
This research focuses not on the body’s ability to process alcohol, but what’s going on in the brain that makes people enjoy it.
In Radcliffe’s demonstration, which he sometimes does live but also by showing a video he filmed a few years ago, two lab mice are hanging out in a cage on a stainless steel lab table. One right after the other, they are injected in their bellies with a syringe of ethanol-saline solution — the equivalent of giving a human who has never had alcohol before 15 drinks all at once.
“For you and I, if you did that with us, we’d be dead,” he says.
The lab mice are similar except in one important way: they are descendants of two extremes of selectively bred mice, one highly sensitive to alcohol and one not. The selective breeding began about 60 years ago in another researcher’s lab. The mice’s reaction to alcohol was observed and like mice were bred with each other, creating two sets of mice — highly sensitive and hardly sensitive at all.
The two mice in Radcliffe’s experiment each receive their shot of alcohol and the timer starts.
“One minute in, they start looking a little intoxicated, if you know what an intoxicated mouse looks like,” the professor says. “They are a little tipsy. They are a little wobbly when they are walking around.”
At 13 minutes in, the very sensitive mouse can’t right itself after the lab technician places it on its back in a plastic tray. The mouse lethargically tries to pump one leg across its belly to flip over, but the attempts are futile. The mouse gives up and lays there.
Meanwhile, the other mouse can right himself with ease. “He’s a little less anxious,” Radcliffe observes. “He’s much more relaxed and he’s willing to get out and explore around.” If the mouse wasn’t drunk, Radcliffe expects it would hide in the back corner of the lab table behind the cage, nervous about being in a new place.
Mice can metabolize food and drink, including alcohol, faster than humans. “These guys will recover, they might have a little bit of a hangover,” Radcliffe says. “They will be fine.”
Other mice, though, are sacrificed during alcohol-related experiments.
In a related experiment, Radcliffe gives mice alcohol and observes their behavior. After about eight hours, he removes their heads and examines their brains. He tries to determine how the neurons in a mouse brain were changed by the alcohol, which is a toxin.
Here is an oversimplified explanation: the RNA and proteins in cells are constantly changing, reacting to their environment to find equilibrium. As a brain learns something new, proteins are formed to help develop and consolidate memories or adjust to change. And when a person — or a mouse — consumes alcohol, proteins respond.
Radcliffe and his team, by comparing the brains of mice that had alcohol to those that did not, have been able to correlate those cell changes in intoxicated mice with changes in their behavior.
A study in 1980 found a similar correlation among people. A University of San Diego researcher named Marc Schuckit gave alcohol to two groups of people — one with a family history of alcoholism and one without. Despite drinking the same amount, people with a family history of alcoholism reported feeling less intoxicated.
Another group of researchers offered mice — nocturnal animals — food and water for 22 hours per day, but nothing but a bottle of alcohol for two hours during the night. Mice that like to drink would sip from the alcohol bottle, gradually increasing their consumption over the course of several days. Mice that are sensitive to alcohol and don’t like to drink, however, ignored the alcohol.
Mice that liked to drink would get intoxicated, but never to the point of passing out, which is typical in all alcohol-related mice experiments. Researchers can make mice dependent on alcohol, by giving them no other sustenance except one spiked with alcohol, but left to their own will, mice do not become addicted.
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Alcoholism is a human condition.
“There is not really a model of alcoholism in rodents,” Radcliffe said. “Alcoholism is just as much a cultural, human anthropomorphic thing because we do have these stresses and we dwell on these stresses. Animals, their big stress of the day might be getting chased by a coyote, and if they survive that, it’s over and they don’t think about it anymore.”
In humans, genetics make people more prone to alcohol addiction, but psycho-social factors — including life stressors, childhood abuse, early exposure to alcohol, anxiety and social acceptance — also play a role, said Dr. Amy Wachholtz, an associate professor of psychology and director of the clinical health psychology Ph.D. program at CU Denver.
A person’s genetics might make them “derive more pleasure from having that drink,” she said.
But even people without the “alcoholism gene” can become addicted if all of their friends binge drink on Friday nights, unlike mice, Wachholtz said. “The mice don’t go, ‘Come on, buddy, have a drink. All the cool kids are doing it,’” she said.
The point of Radcliffe’s research, which is funded by the National Institutes of Health, is to help develop better medications and treatment for alcoholism. Today, there are few medications specifically to treat alcohol addiction — one a daily pill that blocks an enzyme and makes a person feel sick if they consume alcohol.
If researchers can determine what makes brains respond differently to alcohol, they might find that drugs used to treat other illnesses of the brain might also work to treat alcohol addiction.
But the work is complex, and still holds many unknowns. “It’s not a single gene,” Radcliffe said. “It’s dozens or even hundreds of gene variants, and each one has a small effect.”
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