Drunken fruit flies have led to the discovery that insulin may determine susceptibility to alcohol. If confirmed in humans -- and the two species share about two-thirds of their genes -- the finding suggests a promising way to treat alcoholism using drugs that control insulin activity.
The finding by scientists at UCSF was published online Dec. 12 by Nature Neuroscience in advance of publication in the journal.
The UCSF researchers showed that when the normal function of insulin-like molecules in the brain of fruit flies is reduced, the intoxicating effect of alcohol increases. Earlier research has demonstrated that the flies and humans display many of the same vulnerabilities and behavioral responses to alcohol.
"This finding opens promising new avenues for the treatment of alcoholism," said Ulrike Heberlein, PhD, UCSF professor of anatomy and senior author on the paper. "Insulin is already known to act in the nervous system to regulate food intake, so it makes sense that it would influence the response to other substances the body senses as rewards, such as alcohol or drugs of abuse."
Insulin functions in the brains of animals from worms to mammals, and the pathway by which it influences behavior has been conserved throughout millions of years of evolution, Heberlein said, and research has recently revealed that insulin reduces the presence of the molecule that transports dopamine in the brain.
"In animals and humans, dopamine in the brain affects the response to both food and drugs. We are starting to see that in addition to its importance in sugar metabolism, insulin regulates release of neurotransmitters and may be crucial in determining the response to addictive drugs."
In her pioneering 10-year research effort to determine the genetic basis of alcohol-induced behavior, Heberlein has employed an apparatus she calls the inebriometer, in which normal flies and those with known mutations are placed at the top of a four-foot high column and exposed to ethanol. The genetic influence of alcohol sensitivity is measured by how quickly the different genetic types of flies lose their grip and fall to the bottom of the device.
Heberlein has observed that the flies' behavior mimics many of the hallmarks of inebriated humans: heightened activity at first, then faltering coordination, followed by sluggish behavior, and, eventually, passing out if they are exposed to too much alcohol.
She and her colleagues showed earlier that a molecule in the body known as Protein Kinase A modulates sensitivity to alcohol. When its activity is inhibited, the amount of alcohol needed to cause inebriation decreases. The scientists had also examined different regions of the fly brain to determine where the Protein Kinase had its effect. In the new research they zeroed in on a small group of neurons in the brain, specifically cells producing so-called insulin-like peptides, or DILPs.
The scientists also tested flies with genetic defects in the brain receptors that docks with the insulin molecule to trigger the normal signaling function. They found that in all cases, the mutant flies showed increasing alcohol sensitivity, leaving little doubt that the insulin pathway normally functions to regulate the degree of alcohol intoxication.
The key part of the insulin signaling pathway that affects alcohol sensitivity could be the insulin molecule itself, its receptor or processes "upstream" or "downstream" of the insulin-receptor interaction, the scientists pointed out. Drugs already exist that could modify the signaling in the pathway and thereby modify the response to alcohol.
The scientists now want to study whether insulin acts in the brains of mice to affect the rewarding properties of abused drugs. If this turns out to be the case, it would make a compelling case for studying the potential connection between brain insulin and drug addiction in humans, Heberlein says.
Significantly for potential therapy against alcoholism, the increased alcohol sensitivity brought on by changes in brain insulin activity did not affect other behavior, suggesting that interfering with the brain insulin pathway may not pose any serious side effects.
Lead author on the paper is Ammon Corl, a PhD student in Heberlein's lab. Aylin D. Rodan, MD and PhD, a former PhD student in the lab was a collaborator on the research and co-author on the paper.
The research is supported by the National Institutes of Health and the McKnight Foundation for Neuroscience.
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