A team of scientists at The Scripps Research Institute (TSRI) has discovered that a brain protein plays a key role in controlling binge drinking. In the study, the team 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. The results also showed that boosting the protein may prevent drinking to the point of intoxication.
Assistant Professor Candice Contet (right) and Research Associate Melissa Herman were among the authors of the new paper.
"Alcohol hits a lot of different targets in our brain, which makes disentangling the in vivo effects of alcohol quite complicated," said TSRI biologist Candice Contet, senior author of the study. "Our study sheds light on the molecular mechanisms implicated in binge drinking."
According to the U.S. Centers for Disease Control and Prevention, binge drinking – defined as drinking to the point of intoxication – puts people at greater risk for health problems such as cardiovascular disease, liver disease and neurological damage.
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.
GIRK3 knockout mice and controls did show 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 researchers 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 – a condition under which mice did not get intoxicated, pointing to a role for GIRK3 specifically in binge drinking.
The researchers then turned their attention to a neural circuit that facilitates reward seeking. Alcohol, like other drugs of abuse, activates this pathway, which originates in an area of the midbrain called the ventral tegmental area (VTA) and releases the neurotransmitter dopamine in two forebrain areas. The baseline activity of the pathway was not affected by GIRK3 deletion; however, the neurons became completely insensitive to alcohol's activating effect without GIRK3, suggesting that GIRK3 knockout mice drink more ethanol to boost the engagement of neural pathways mediating alcohol's rewarding effects.
Interestingly, injecting a GIRK3-expressing virus in the VTA of knockout mice brought their alcohol consumption down to normal levels, and normal mice expressing more GIRK3 in the VTA drank even less. This leads the researchers to believe that a compound selectively targeting GIRK3-containing channels may hold promise for reducing alcohol consumption in heavy binge drinkers.