The study was authored by Adrian Rothenfluh, Ph.D., and colleagues in the laboratory of Ulrike Heberlein, Ph.D., at UCSF, in collaboration with researchers at the Ernest Gallo Clinic & Research Center. The scientists examined the behavior of fruit flies (Drosophila) exposed to alcohol. Ordinarily, at low doses of alcohol fruit flies increase their activity, while high doses have a sedative effect. However, the researchers found some fruit flies were much more resistant to alcohol sedation. These flies continued to move about much longer than typical fruit flies exposed to the same amount of alcohol. The scientists subsequently identified key differences in a particular gene associated with this behavior. The mutation also altered the flies’ sensitivity to cocaine and nicotine as well. Because this gene variant affected the behavioral response to substances of abuse, the researchers dubbed it white rabbit — a reference to the title of a 1960s song about drug-induced changes.

The researchers exposed fruit flies to vaporized alcohol and monitored their behavior and motion patterns with sensitive tracking instruments. They isolated the flies that were less sensitive to alcohol’s sedative effects. By breeding subsequent populations of mutant flies, the scientists identified the particular genetic mutation.

The researchers further showed that the white rabbit mutation disrupted the function of the RhoGAP18B gene. They also isolated a number of gene variants of RhoGAP18B, each of which had a distinctly different effect on the response to alcohol. Manipulating these genetic variants, the researchers generated flies with greater and lesser sensitivity to alcohol’s sedative and stimulant effects. The findings have implications for researchers seeking corresponding genes and molecular pathways in other animal models and humans.