Scientists hope ‘supermouse’ can’t get drunk
Lexington Herald Leader
By Marty Toohey
November 30, 2015
A group of University of Texas researchers think they could unlock new treatments for alcohol abuse with a novel experiment: creating a “supermouse” that cannot get drunk.
The difficulty treating the often-debilitating symptoms of alcohol abuse stems partly from an incomplete understanding of the biology behind drunkenness, according to the research team. A supermouse, they hope, could reveal information that could improve treatment for alcoholism.
“Right now, believe it or not, scientists still don’t know the answer to the fundamental question of how we get drunk,” said Jon Pierce-Shimomura, a neuroscience professor who oversees a lab at UT that investigates genetic disorders. “What we’re excited about is the potential for treating people at the point . where they’re really vulnerable because they’re dealing with these often-intense withdrawal symptoms.”
The supermouse project, first reported by The Daily Texan, would be a next step in research into what happens with alcohol abuse at the molecular level. The team is trying to raise $12,000 through UT’s crowdsourcing platform to launch the project.
Many labs are experimenting with genetic strains in mice, said Jonathan Chick, chief editor of the Alcohol and Alcoholism medical journal. Researchers at the University of Tennessee, for example, are working on similar research about how alcohol affects mice, he told the Austin American-Statesman (http://atxne.ws/1If8Ei4).
When people drink, some alcohol passes into the bloodstream, then into the brain, glomming onto the receptors that help send and receive information. This essentially gums up the neural circuitry, suppressing the release of some chemicals and stimulating the production of others, such as pleasure-causing dopamine and endorphins.
Thus the mixed bag of alcohol effects: loss of inhibition, loss of balance and euphoria, among others.
Still, unlike drugs such as cocaine, which target a specific part of the nervous system, alcohol has many targets. Remaining questions include which targets are associated with effects such as increased tolerance; what causes the ethanol to glom onto particular receptors; and why the body has withdrawal symptoms such as the shakes, fever and, in severe cases, hallucinations or seizures.
To the UT researchers, the answer starts with evidence that different animals get drunk on alcohol from about the same dose (as anyone whose cat has gotten into a glass of wine can attest).
A decade ago, Pierce-Shimomura, then a postdoctoral fellow at the University of California at San Francisco, was part of a team that did testing on worms, which have many of the same genes as humans. The researchers found, to their surprise, that only one of the worms’ genes was central to the effects of drunkenness. That gene was responsible for the production of a protein that was activated by alcohol; once that protein was activated, the worms grew sluggish and had lower brain function. When the researchers manipulated the gene so that it kept the protein activated, the worms became drunk and remained that way, even without alcohol.
Last year Scott Davis, a neuroscience graduate student at UT, took the research one step further. He found that a particular type of induced mutation could keep the protein from activating, resulting in “mutant worms” that do not get drunk, according to research published in The Journal of Neuroscience.
When Davis and other researchers switched a relevant worm gene with its counterpart from humans, they achieved the same results: the “humanized” worm still did not get drunk. More recently, they discovered the mutation also reduces the symptoms of alcohol withdrawal.
Still, the way people act when drunk is complicated, with far more variables than a worm, said Luisa Scott, a research associate at the lab Pierce-Shimomura runs. Worms alone cannot be used to test the protein’s role in behaviors such as cravings. Another issue: preventing alcohol from activating the protein while also ensuring that the protein can still carry out other biological roles, such as helping regulate sleep cycles, balance and blood pressure, Scott said.
Thus the need to experiment on a more complicated animal: a mouse with the same mutation.
Pierce-Shimomura and his colleagues on the supermouse projects are working through UT’s Waggoner Center for Alcohol and Addiction Research, along with Oregon Health and Science University researcher (and UT alumna) Angela Ozburn.
If they are able to raise the funding, the researchers would engineer a supermouse at UT’s Mouse Genetic Engineering Facility. They would tweak a gene in mouse embryos, which would then be implanted in a mother and observed once born.
A simple example of the possible tests the UT team hopes to conduct: A drunken mouse that is on its back cannot normally turn over. Could it flip over if the protein is kept from activating?
“From a basic research perspective, there is a lot that this would help with,” Scott said.
Still, the researchers say the most likely outcome is a base from which to find treatments for alcohol withdrawal — and the symptoms that can make avoiding a relapse so challenging.
About 17 million American adults have an alcohol-abuse disorder, according to the National Institutes of Health. Of those treated for alcohol problems, about one-third “have no further symptoms one year later,” and “many others substantially reduce their drinking and report fewer alcohol-related problems,” according to the institute.
To the supermouse researchers, that leaves about two-thirds of the people who seek treatment dealing with symptoms a year later. Those numbers also miss relapsed alcoholics who have simply stopped seeking treatment because they can’t get past the withdrawal symptoms.
“Many of the people we’re talking about are frequent fliers,” Pierce-Shimomura said. “People who need a drink just to start the day. We think that a better understanding of why alcohol affects us the way it does could lead to help for them.”