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Neuroscientists Find a Possible Off Switch for Booze Tolerance

A drug called THIP turns hard-drinking mice into teetotalers without apparent side effects.

There's more to watching people get loaded than the climactic blooper reel—you know, when things start getting weird as excess booze is converted into awkward aggression, highly regrettable opinions, and basically just falling all over the place. There's the whole progression of it, from the first posturings of overconfidence to anecdotes and jokes that segue to rambling monologues and tirades to those distinctive moments when people start realizing they've had enough. And then have some more. Drinking is really a whole big process of progressive loosening.

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But it's different for different people, right? This is what we often call tolerance. Some people can just keep it together longer. And it's in these variations in keeping it together that researchers hope to find new ways to attack alcoholism.

To this end, a study published in the Journal of Neuroscience from researchers at Washington State University and Oregon Health and Science University describes a mechanism that strongly predicts whether or not an animal is likely to drink a lot of alcohol. It has to do with how quickly booze impairs the part of the brain responsible for motor functioning. In mice where this impairment happens quickly, the drive for consuming more alcohol goes away before drinking escalates into binging. In mice who are less sensitive to these effects, drinking is more likely to become binge drinking. This seems pretty obvious, but there's more to it.

This has to do with granule cells found in the cerebellum, the part of the brain responsible for motor control. These cells, which are among the smallest and most numerous in the brain, serve an excitatory function. That is, they increase the probability of signals being fired across cerebellum. If they're inhibited, so too are the brain's motor functions. The effect might wind up looking a lot like drunkenness.

The exteriors of cerebellar granule cells are outfitted with small proteins functioning as receptors for gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the mammalian brain. When these receptors start lighting up, the effect is of turning down the granule cells, and, thus, of slowing down the mammal's motor functioning. This is what booze does to the cerebellum.

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In an earlier study published in Nature Neuroscience, much of the same team behind the current paper, led by WSU neuroscience professor David Rossi, described experiments with two different breeds of mice featuring GABAA receptors with differing responses to alcohol. Those with GABAA receptors that were suppressed by alcohol—whose granule cells were less inhibited—showed a higher predilection for drinking a lot. Simply, mice were able to drink for longer and remain functional, as demonstrated by their ability to hang out on a rotating cylinder and not fall all over.

The new study took the hard-drinking phenotype of mice from the earlier work, those that could continue drinking while on the rotating cylinder, and injected them with a drug called THIP. This had the effect of lighting up their GABAA receptors, which then had the booze-like effect of depressing signaling activity among the excitatory granule cells. The hard-drinking mice suddenly became teetotalers, relatively speaking, and stopped drinking at "recreational" levels.

It sounds a bit like we're just making mice not want booze by getting them drunk, which isn't the case. In triggering the right GABAA receptors, the researchers found that they could get the mice to stop wanting alcohol without necessarily having the same falling-down-everywhere effects. The reasons for this are something of a mystery.

"The best answer I can hypothesize—but currently lack data to support—is that we injected THIP into a subregion of the cerebellum, whereas alcohol that is consumed obviously affects the whole cerebellum," Rossi told me. "So, one idea is that the sub region of the cerebellum that we injected into may play a role in consumption of rewarding substances, but may play a lesser role in motor control."

"The cerebellum is actually involved in many processes beyond motor coordination," he said. "So, while the incoordination caused by alcohol may be the actual deterrent for continued drinking, it could also just be a correlate that indicates differential impacts on the cerebellum, with the actual deterrent mechanism being due to other cerebellar processes, something we are currently working on."

So, yes, we still have a ways to go here. Before we can start promising effective pharmacological treatments for alcoholism, we need to know exactly what's going on—that is, why the mice stop drinking if it isn't because of motor impairment. For now, boozing will in some part remain a mystery.