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Sexually Rejected Flies Turn to Booze

Offer a male fruit fly a choice between food soaked in alcohol and its nonalcoholic equivalent, and his decision will depend on whether he's mated recently or been rejected by a female. Flies that have been given the cold shoulder are more likely to go for the booze, researchers have found. It's the first discovery, in fruit flies, of a social interaction that influences future behavior.

"This is an amazing link," says neurogeneticist Troy Zars of the University of Missouri, Columbia, who was not involved in the study. Understanding the brain pathways responsible, he says, could help explain more broadly how rewarding behavior is reflected in the brain, and how the brain mediates complex behaviors.

Scientists already knew that when fruit flies drink alcohol, reward pathways in their brains are activated, making it a "pleasurable" experience. They also knew that social interactions are among the most rewarding experiences. So researchers led by neuroscientist Galit Shohat-Ophir, who conducted the work at the University of California, San Francisco, but who has now moved to the Howard Hughes Medical Institute's Janelia Farm Research Campus in Ashburn, Virginia, wanted to see whether the two types of rewards were connected in the brain. "This was just a wild experiment to do," she says. "We didn't expect to see such dramatic results."

The scientists put 24 male fruit flies (Drosophila melanogaster) in one of two situations. Half the males were placed in vials in groups of four, each group with 20 female flies that were ready to mate, allowing the males to mate with multiple females. The other half of the males were put alone in vials, each with one female that had already mated, making her reject any courtship advances. After 4 days of repeated mating or rejection, the male flies were moved to new containers, with capillaries containing food mash—some with alcohol and others without—that they could eat. Each fly could chose which capillary to drink from, and the researchers measured the amount that was consumed.

The researchers expected all of the flies to prefer alcohol, but that's not what they found. "You see that the mated males actually have an aversion to the alcohol-containing food," Shohat-Ophir says. "And the rejected males have a high preference to that food with alcohol." On average, the rejected males drank four times more alcohol than the mated ones, her team reports online today in Science.

Shohat-Ophir and colleagues suspected that a chemical in the brain called neuropeptide F (NPF) might play a role in the link, as it's been previously discovered to mediate alcohol preference. So they measured the levels of NPF in the flies' brains after mating or after rejection by a female. The rejected males, they found, had half the amount of NPF in their brains. If the researchers lowered the levels of the NPF receptors in the brain, males that had mated acted like those that were rejected, drinking more ethanol-containing solution. And in the reverse experiment, if the team activated the NPF cells in the brain, rejected male flies no longer preferred the alcohol-laden food.

Shohat-Ophir says the take-home message is that experiences are translated into a molecular signature through levels of NPF. In turn, those NPF levels drive behavior—either drinking or not drinking—that will restore the reward system to normal levels.

"They showed that NPF is necessary to mediate this link between sex and alcohol, and also that NPF is sufficient for the association," Zars says. "That's two strong arguments that this is a real connection and not mediated in some other way."

But there are still questions, Zars says, about how the connection works at a molecular level. How does the reward of a sexual experience control NPF levels? How do NPF levels control alcohol consumption?

In addition, there is a protein in mammals, including humans, that is similar to NPF, called neuropeptide Y (NPY). Studies have shown that people with depression and post-traumatic stress syndrome have lower levels of NPY. Moreover, lower NPY levels have been linked to alcohol and drug consumption in rats, and certain gene variants of NPY found to be more common in human alcoholics. But whether NPY can be mediated by social experiences has yet to be studied. "Our results certainly don't translate directly from flies to humans," Shohat-Ophir says, "but it does bring up questions and suggest future studies."