Drunken Fruit Flies Reveal Molecular Pathway Regulating Sensitivity To Alcohol

The study, reported in the June 12 issue of Cell, and praised in an accompanying review by Howard Hughes Medical Institute Investigator Hugo J. Bellen, DVM, PhD, "lays the foundation for a genetic approach to dissecting the acute, and possibly the chronic, effects of alcohol," said Bellen, and "should increase our understanding of the molecular mechanisms causing drug abuse and addiction in the near future."

The finding, which sheds light on how fruit flies become drunk, aims to address in the future what makes some people more apt to become alcoholics. Previous studies have determined that people who are less sensitive to alcohol's impact are at greater risk for becoming alcoholics, and that the degree of sensitivity to alcohol is genetically influenced. Young men with a family history of alcoholism, for instance, are less sensitive to alcohol than those from families without alcoholism. But researchers have been unable to determine the biological explanation for the relationship between a sensitivity to alcohol and a risk for alcoholism.

In the fruit fly, or Drosophila (Dra-SOPH-i-la), study, led by Ulrike Heberlein, PhD, an assistant professor of neurology at UCSF and an investigator in the Ernest Gallo Clinic and Research Center at the UCSF-affiliated San Francisco General Hospital, the researchers sought to determine what molecular factors influence a fruit fly's sensitivity to alcohol. They set about this challenge by "knocking out," or removing, different genes from the fruit flies and then exposing the animals to alcohol as a way of revealing the role the missing genes would normally play.

When they knocked out a gene known as amnesiac, the flies became more sensitive, or more inebriated, than their brethren. More importantly, however, when the researchers examined how the amnesiac gene normally functions within the fruit fly's neural system, they determined that it regulates the cyclic AMP (cAMP) pathway, a signal transduction cascade that scientists at the Gallo Center have long known was affected by alcohol through studies in human cells. This discovery fit with a previous finding, namely that amnesiac is believed to encode a molecule that stimulates cAMP production.

The scientists thus deduced that the fruit flies missing the amnesiac gene had reduced cAMP production, and that this action caused greater intoxication. To test their hypothesis, they treated the mutant amnesiac flies with agents that increased cAMP levels and were able to reverse the alcohol sensitivity. The finding made a giant leap from an isolated gene in fruit flies to an entire molecular pathway previously observed in animal and human cell cultures.

"This was an exciting discovery," said Heberlein. "We've known cAMP was involved in the brain's response to alcohol, but we haven't known what role it plays in causing the behavioral effects associated with intoxication. Our study demonstrates that proper regulation of the cAMP signaling pathway is central to establishing ethanol sensitivity in Drosophila."

The finding does not suggest that the amnesiac mutation exists in humans, nor that any one gene affects sensitivity to alcohol in higher animals. The significance, said Heberlein "is that we have found a pathway that modulates the response to alcohol."

"Our next step, she said, "is to identify more genes in fruit flies associated with alcohol behaviors and to see if we can find homologous, or similarly acting, genes in higher organisms, including mice and humans." Ultimately, of course, if these genes do exist in humans the researchers hope to find that they are linked to alcoholic behaviors.

Given how strikingly similar the fruit flies' behavioral response to alcohol is to the human response, said Heberlein, this may well happen, for the similarity indicates that the genes that regulate these behaviors have not changed significantly in the evolutionary process, suggesting a common molecular pathway may be in place.

The UCSF laboratory, part of UCSF's new Neurobiology of Addiction Center, which includes the Gallo Center, is the only institute in the world using Drosophila as a system for studying the genetics of alcoholism. The UCSF study was funded by grants from National Institute on Alcohol Abuse and Alcoholism (NIAAA), the Alcoholic Beverage Medical Research Foundation and the March of Dimes Birth Defects Foundation.