Summary: Researchers have created the first fruit fly model of cocaine addiction by genetically altering flies so they will voluntarily consume cocaine. Normally, fruit flies avoid cocaine because it triggers bitter taste receptors. By silencing those bitter-sensing pathways, the team produced flies that develop a clear preference for low-concentration cocaine in sugar water within about 16 hours of exposure.
This new Drosophila model offers a fast, efficient system to screen genes and neural mechanisms involved in cocaine use disorder. Since many addiction-related genes are conserved between flies and humans, the model could accelerate identification of therapeutic targets for treating cocaine addiction.
Key Facts:
- Fruit fly addiction model: Genetically modified Drosophila can self-administer cocaine, providing a laboratory model of drug preference.
- Bitter taste blockade: Disabling bitter-sensing neurons or mutating the Gr66a bitter receptor removes innate cocaine aversion and allows consumption.
- Rapid screening potential: The model makes it possible to test many candidate genes and mechanisms quickly to inform mammalian studies and therapeutic development.
Source: University of Utah
For the first time, scientists have engineered fruit flies that will self-administer cocaine under choice conditions.
This model is a promising tool for developing new treatments to prevent and treat cocaine use disorder, a serious public health issue that affects a substantial number of people. By leveraging the genetic tractability and short life cycle of fruit flies, researchers can rapidly investigate how specific genes and neural circuits contribute to addiction-related behaviors.
Genetics plays a large role in the risk of developing cocaine use disorder, but the many genes involved have made it difficult to single out the best targets for treatment. A Drosophila model that reliably shows experience-dependent cocaine preference allows rapid functional testing of candidate genes before moving to more complex animal models.
The study appears in the Journal of Neuroscience.
Why fruit flies?
Fruit flies and humans respond to cocaine in surprisingly similar ways at the behavioral level. At low doses, both species often exhibit increased activity or agitation, while higher doses can lead to incapacitation. Drosophila shares a large proportion of genes linked to human disease, and researchers have previously used flies successfully to uncover mechanisms behind other substance use disorders.
Because flies reproduce and develop quickly and are amenable to high-throughput genetic manipulation, they are an excellent early-stage model for probing the biology of addiction and prioritizing genes for follow-up in mammalian systems.
However, a major obstacle stood in the way: wild-type flies naturally avoid cocaine. When offered a choice between plain sugar water and sugar water laced with cocaine, unmodified flies consistently chose the drug-free option, even after prior exposure.
The bitter barrier
The research team investigated the flies’ taste system and found that cocaine strongly activates bitter-sensing gustatory neurons located on the tarsal segments (the fly’s “feet”). These receptors evolved to help insects avoid plant toxins, and cocaine acts as such a deterrent.
When the investigators silenced the bitter-sensing neurons or inactivated the Gr66a bitter receptor, flies no longer experienced cocaine as aversive. Under those conditions, flies began to prefer sugar water containing low concentrations of cocaine over plain sugar water, developing a measurable preference within roughly 12–18 hours from first exposure.
The preference emerged only at low cocaine concentrations that did not cause incapacitation, highlighting the importance of dose in modeling voluntary drug consumption.
From fly behavior to human impact
By enabling experience-dependent cocaine self-administration in Drosophila, this model opens the door to large-scale genetic screens to identify variants and pathways that increase or decrease risk of cocaine use disorder. Findings from fly studies can be forwarded to researchers using mammalian models, helping to narrow the field of candidate targets for therapeutic development.
As the study’s first author notes, the speed and scalability of fly experiments permit researchers to uncover risk genes that would be challenging to isolate in more complex organisms. The senior author emphasizes that understanding the mechanisms of cocaine choice at a basic level increases the chances of finding interventions that act on those mechanisms.
Beyond targeted drug discovery, basic research into how simple brains encode choice and reward can yield unexpected insights relevant to human neuroscience and mental health.
The paper is titled “Bitter sensing protects Drosophila from developing experience-dependent cocaine consumption preference” and is published in the Journal of Neuroscience.
Funding: This work was supported by the Huntsman Mental Health Institute, the University of Utah Molecular Medicine Program, and the National Institutes of Health, including grants from the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK110358), the National Institute on Drug Abuse (K01DA058919, R21DA049635, R21DA040439), and the National Institute on Alcohol Abuse and Alcoholism (R01AA026818, R01AA019536-S1, R01AA030881). The content is the responsibility of the authors and does not necessarily reflect official NIH views.
About this genetics and addiction research news
Author: Sophia Friesen
Source: University of Utah
Contact: Sophia Friesen – University of Utah
Image: The image is credited to Neuroscience News
Original Research: Closed access. Title: “Bitter sensing protects Drosophila from developing experience-dependent cocaine consumption preference” by Adrian Rothenfluh et al., Journal of Neuroscience. DOI: 10.1523/JNEUROSCI.1040-24.2025
Abstract
Bitter sensing protects Drosophila from developing experience-dependent cocaine consumption preference
Cocaine is a powerful psychostimulant with high addiction potential, and susceptibility to cocaine use disorder is strongly influenced by genetic factors. Progress toward effective pharmacological treatments has been limited, in part because the specific genes and neural mechanisms that drive the transition to problematic use are not well understood.
Drosophila has been an effective model for identifying genes and circuits that underlie substance use disorders, particularly alcohol-related behaviors. Although flies show acute responses to cocaine consistent with mammalian intoxication—such as increased locomotion and disrupted sleep—until now there was no established model in which flies show a learned preference for cocaine consumption.
Using consumption assays and a two-choice preference test in male Drosophila, together with genetic and imaging approaches, the authors demonstrate that cocaine is innately aversive through activation of bitter-sensing gustatory neurons expressing the Gr66a receptor. Silencing these bitter-sensing neurons or mutating Gr66a reduces avoidance and allows flies to develop a cocaine-containing solution preference within 12–18 hours, whereas control flies remain averse.
These results indicate that bitter taste normally protects flies from developing cocaine self-administration preference. By removing that protective input, Drosophila can serve as a tractable model to study experience-dependent cocaine consumption and to test human genetic variants linked to cocaine use disorder for causal roles in drug-seeking behavior.