A Mutated Taste Gene Makes Fruit Flies Seek Out Cocaine

The saying “You can catch more flies with honey than with vinegar” evokes an image of irresistible sweetness. Just as flies are drawn to sugar, this craving mirrors the allure of other addictive substances. Fruit flies are often used as model organisms in addiction research, as they display behavioral responses to substances like alcohol that closely resemble those seen in humans. But what about more potent drugs, such as cocaine, where the risk of developing cocaine use disorder (CUD) is known to have a strong genetic component?¹

“We have previously modeled alcohol self-administration in fruit flies, and this has revealed that humans and fruit flies share many of the same genes that drive alcohol consumption and addiction,” said Adrian Rothenfluh, a molecular neuroscientist at the University of Utah in a press release. “So, it is reasonable to think that the genes involved with cocaine addiction in humans may also be involved in this fruit fly model.” While other studies have identified putative risk genes for CUD, the researchers aimed to investigate genes and molecular mechanisms that might influence flies to preferentially self-administer cocaine.²

Rothenfluh’s team discovered that fruit flies naturally avoid cocaine because it activates their bitter taste receptors. When they mutated a gene for these receptors, the fruit flies preferred cocaine over a sucrose solution. These findings, published in the Journal of Neuroscience, demonstrate the potential of fruit flies as a model for identifying the genetic mechanisms underlying CUD.³

The researchers first assessed cocaine consumption and preference in normal fruit flies. They mildly food-deprived the flies and offered them a sucrose solution with varying concentrations of cocaine. As cocaine levels increased, the flies avoided the solution and ate less. This led the researchers to ask: How could they get fruit flies to prefer cocaine?

Before flies eat, they use signals from multiple sensory organs, such as their proboscis—a straw-like appendage—and their legs, which contain gustatory sensory neurons that express the Gr66a bitter receptor. Since cocaine is an alkaloid, which most flies detect as bitter, the researchers suspected that bitter taste receptors triggered their aversion to the drug.

The researchers observed that flies often taste food with their legs first, allowing them to detect substances before feeding. Using enhanced green fluorescent protein to visualize neuronal activity, the team confirmed that flies indeed sensed cocaine in their legs through the Gr66a neurons and were often less willing to consume bitter cocaine-sucrose solutions.

Next, the researchers tested whether reducing the flies’ bitter perception would increase cocaine consumption preference. In another 24-hour feeding assay, both Gr66a mutant flies and those with electrically silenced Gr66a neurons were given the feeding solutions. Both groups showed less aversion to the drug and began preferring the cocaine-sucrose solutions over plain sucrose within 12–18 hours. These findings demonstrate that bitter-sensing receptors protect flies from consuming cocaine, but genetic modulation can alter their preference for cocaine over sucrose.

Although Gr66a is specific to flies and is not found in humans, genetically modified fruit flies can serve as a powerful model in studying cocaine self-administration preference. Further investigations may explore previously identified human gene variants linked to CUD.