Researchers at The Scripps Research Institute (TSRI) have discovered that a brain protein has a key role in controlling binge drinking in animal models. They found that deleting the gene for this protein in mice ramped up alcohol consumption and prevented the brain from signaling the rewarding properties of alcohol.
“Alcohol hits a lot of different targets in our brain, which makes disentangling the in vivo effects of alcohol quite complicated,” said biologist Candice Contet, Ph.D., senior author of the study. “Our study sheds light on the molecular mechanisms implicated in binge drinking.”
The TSRI paper (“GIRK3 gates activation of the mesolimbic dopaminergic pathway by ethanol”) is published in the Proceedings of the National Academy of Sciences.
The goal of the new study was to identify the role of a member of the “G protein-gated inwardly rectifying potassium channel” (GIRK) family in the behavioral and cellular responses to alcohol. GIRK channels are distributed throughout the nervous system, where they decrease the excitability of neurons, making them less likely to fire. Studies in isolated cells have revealed that alcohol can directly activate GIRK channels; however, scientists did not know whether this action matters for the behavioral effects of alcohol.
In the new study, Dr. Contet and her colleagues decided to focus on the GIRK3 subunit, which had previously been shown to modulate the effects of other drugs, such as the “date rape drug” γ-hydroxybutyrate (GHB) and cocaine. The researchers investigated how GIRK3 influenced mouse behavior and neuronal function in the presence of alcohol. To do so, they compared “knockout” mice missing GIRK3 with normal mice.
The researchers first found that the deletion of GIRK3 did not impact alcohol metabolism and did not affect how sensitive mice were to alcohol intoxication. Mice lacking GIRK3 and their normal counterparts cleared alcohol from their blood at the same rate, and experienced a similar loss of balance, sleepiness, and reduced body temperature in response to alcohol.
However, in agreement with results from a previous study, the researchers found that GIRK3 knockout mice experiencing alcohol withdrawal failed to display the typical handling-induced convulsions caused by neuronal hyperexcitability.
GIRK3 knockout mice and controls also showed differences in alcohol intake in a test mirroring human behavior during a “happy hour” at a bar. In this test, mice were given access to ethanol for only two hours a day, at a time when they were most likely to drink to the point of intoxication.
The team found that GIRK3 knockout mice consumed much more alcohol than the control group. This effect was not observed when mice were given continuous access to alcohol, conditions under which mice do not get intoxicated. This result pointed to a role for GIRK3 specifically in binge drinking.
Overall, the new study showed that more GIRK3 in the ventral tegmental area of the midbrain reduced binge drinking. This has led the researchers to believe that a compound selectively targeting GIRK3-containing channels may hold promise for reducing alcohol consumption in heavy binge drinkers.