TSRI scientists link GIRK3 to binge drinking

“Alcohol hits a lot of different targets in our brain, which makes disentangling the in-vivo effects of alcohol quite complicated,” said TSRI biologist Dr. Candice Contet, senior author of the study. “Our study sheds light on the molecular mechanisms implicated in binge drinking.”

The aim of the new study was to identify the role of a member of the G protein-gated inwardly rectifying potassium channel (GIRK) family in behavioral and cellular responses to alcohol. GIRK channels are allocated throughout the nervous system; they decrease the excitability of neurons, making them less likely to fire. Contet and her colleagues focused on the GIRK3 subunit, which had previously been shown to modulate the effects of other drugs, such as γ-hydroxybutyrate (GHB), cocaine and morphine. The researchers examined GIRK3 and its influence on mouse behavior and neuronal function in the presence of alcohol. To do so, the study compared knockout mice missing GIRK3 with normal mice.

The deletion of GIRK3 did not impact alcohol metabolism or sensitivity to alcohol intoxication. But GIRK3 knockout mice and control mice did show differences in alcohol intake in a test mirroring human behavior during “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 in which mice do not get intoxicated. This result alluded to GIRK3’s role in binge drinking.

Contet and her colleagues considered two possibilities. “Mice lacking GIRK3 could be drinking more because they feel more pleasure from alcohol and are therefore more motivated to drink—or they could be drinking more because they feel less pleasure and therefore need to drink more to reach the same level of pleasure as normal mice,” said Contet.

To address this question, the researchers turned their attention to the mesocorticolimbic dopaminergic pathway, a neural circuit that facilitates reward seeking. This pathway originates in an area of the midbrain called the ventral tegmental area (VTA) and releases dopamine in two forebrain areas: the ventral striatum and the prefrontal cortex. Alcohol, like other sometimes-abused drugs, activates this pathway. The researchers evaluated the activity of the pathway using two complementary techniques: electrophysiological recordings, which measured the firing of VTA neurons, and microdialysis, which tracked dopamine release in the ventral striatum. In both experiments, the baseline activity of the pathway was not affected by GIRK3 deletion. However, the researchers found that the pathway became completely insensitive to alcohol’s activating effect without GIRK3.

Contet tells DDNews, “We were very surprised that removing a single subunit of GIRK channels, among the many other ion channels found in neurons, completely blocked the ability of alcohol to activate the mesolimbic dopaminergic pathway. This is truly a dramatic effect, and we would like to understand the underlying mechanism. Despite years of investigation, we still don’t know precisely how alcohol gets to excite VTA dopaminergic neurons. Our study pinpoints GIRK3 as a critical player, but we still have a lot to learn about the molecular events mediating the effect of alcohol in the VTA.”

Alcohol was also unable to trigger the release of dopamine in the ventral striatum of GIRK3 knockout mice. Contet believes that, taken together, the results suggest that GIRK3 knockout mice drink more ethanol to boost the engagement of other neural pathways mediating alcohol’s rewarding effects.

“At first sight, our results may seem paradoxical: GIRK3 knockout mice drink more alcohol, but their mesolimbic dopaminergic pathway is completely insensitive to alcohol. If the canonical ‘reward pathway’ of the brain cannot be activated by alcohol, these mice should not have any motivation to drink alcohol,” Contet continues. “But the mesocorticolimbic dopaminergic pathway is not the only brain circuit responsible for the rewarding properties of alcohol, and we think that GIRK3-deficient mice end up drinking more alcohol to activate alternative circuits more strongly than normal mice would. The mesocorticolimbic dopaminergic pathway is the focus of numerous, if not most, studies of reward processing. Another take-home message from our work is that there are other brain regions deserving just as much attention if we want to fully understand how the urge to drink alcohol is generated.”

Interestingly, the researchers were able to alter binge drinking in the opposite direction by injecting a GIRK3-expressing virus in the VTA. Reintroducing GIRK3 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 has led researchers to believe that a compound selectively targeting GIRK3-containing channels may hold promise for reducing alcohol consumption in heavy binge drinkers.

“Our hope is that the effect of GIRK3 could be harnessed to help heavy binge drinkers curb their alcohol consumption,” says Contet. “However, in order to design a viable therapeutic strategy targeting GIRK3, we still need to understand the consequences of removing or increasing GIRK3 at the subcellular level. GIRK3 is one of three types of neuronal GIRK subunits, and functional GIRK channels can still form in the absence of GIRK3. A study performed in cultured cells has shown that GIRK3 promotes the degradation of GIRK subunits that co-assemble with it, which means that GIRK3-deficient mice could actually have more of the other GIRK subunits. Another possibility that still needs to be explored is that the incorporation of GIRK3 could enhance or reduce the ability of alcohol to activate GIRK channels. Finally, an important hurdle is that we have yet to find a compound that can selectively activate GIRK3-containing channels.”

“However, with the recent identification of a potent agonist selective for GIRK1-containing channels, this hurdle may soon be overcome,” she adds. GIRK3-containing channels have also been implicated in regulating the sensitivity of VTA neurons to other chemically distinct drugs: GHB, cocaine and morphine. This suggests that a therapeutic strategy targeting GIRK3 could have applications for substance use disorders beyond alcohol binge drinking.”

The study, “GIRK3 gates activation of the mesolimbic dopaminergic pathway by ethanol,” was published in the journal Proceedings of the National Academy of Sciences.