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Gene Therapy Halts Binge Drinking in Rats

A human melanoma cell grown in culture. Anne Weston, LRI, CRUK, all rights reserved by Wellcome Images.

In a series of experiments in rats, researchers gained new insights into the molecular players involved in binge drinking. The findings suggest future therapeutic strategies.

Binge drinking is typically defined as having 5 or more drinks in a row for men, and 4 or more drinks in a row for women. People of all ages can engage in binge drinking, but it’s a particular problem among college students. About 2 of 5 college students — more than 40% — have engaged in binge drinking at least once during the past 2 weeks.

Molecules in the brain called GABA_A receptors are known to be involved in excessive alcohol consumption and have been recognized as potential targets for therapy. The receptor’s α1 and α2 subunits both seem to play a role. A part of the brain called the ventral pallidum is rich with α1 GABA_A receptors, whereas the central nucleus of the amygdala has mostly α2 subunits. Researchers still don’t have a detailed understanding of the roles of these subunits and the molecular pathways they trigger.

A research team led by Dr. Harry June and Dr. Laure Aurelian at the University of Maryland School of Medicine set out to study these GABA_A receptors in an established rat model for binge drinking. They also looked at Toll-like receptor 4 (TLR4), an innate immune system molecule that’s been shown to contribute to the inflammation and brain damage brought on by excessive drinking. Their work was supported by NIH’s National Institute on Alcohol Abuse and Alcoholism (NIAAA) and National Institute of Neurological Disorders and Stroke (NINDS). The study appeared on March 15, 2011, in the Proceedings of the National Academy of Sciences.

The researchers used molecules called small interfering RNA (siRNA), which temporarily “silence” targeted genes in the brain regions in which they are infused. Three to 6 days after silencing α2 in the central amygdala, the rats had virtually no alcohol intake. Their drinking returned to previous levels 13 days after the siRNA infusion, as α2 levels rose once again. Silencing α2 in the ventral pallidum, in contrast, had no effect on the rats’ drinking.

The researchers noted that α2 silencing in the central amygdala significantly lowered levels of TLR4. To test the role of TLR4 directly, the scientists silenced TLR4 in the central amygdala and found that the rats’ binge drinking fell significantly. But as with α2, the rats’ drinking remained unchanged when TLR4 was silenced in the ventral pallidum.

In contrast, silencing α1 in the central amygdala didn’t affect drinking. But drinking was significantly reduced when α1 was silenced in the ventral pallidum.

Taken together, these results suggest that the α2 subunit of GABA_A acts through TLR4 in the central amygdala during binge drinking. The α1 subunit also plays a role in binge drinking, but in the ventral pallidum and independent of TLR4. More research will be needed to better understand how these and other molecules contribute to binge drinking.

Gene therapy or other strategies that target these brain receptors may one day prove effective for fighting binge drinking. “The discovery of this involvement of TLR4 in a pathway with GABA is most remarkable,” Aurelian says. “This study provides basically a totally new understanding of what TLR4 and GABA are all about. That’s exciting, but there is a lot more to learn about this pathway and where it goes beyond this point.”

— by Harrison Wein, Ph.D.