Cocaine chemogenetics blunts drug-seeking by synthetic physiology

Juan L. Gomez, Christopher J. Magnus, Jordi Bonaventura, Oscar Solis, Fallon P. Curry, Marjorie R. Levinstein, Reece C. Budinich, Meghan L. Carlton, Emilya N. Ventriglia, Sherry Lam, Le Wang, Ingrid Schoenborn, William Dunne, Michael Michaelides () and Scott M. Sternson ()
Additional contact information
Juan L. Gomez: National Institute on Drug Abuse Intramural Research Program
Christopher J. Magnus: Howard Hughes Medical Institute; Janelia Research Campus
Jordi Bonaventura: National Institute on Drug Abuse Intramural Research Program
Oscar Solis: National Institute on Drug Abuse Intramural Research Program
Fallon P. Curry: National Institute on Drug Abuse Intramural Research Program
Marjorie R. Levinstein: National Institute on Drug Abuse Intramural Research Program
Reece C. Budinich: National Institute on Drug Abuse Intramural Research Program
Meghan L. Carlton: National Institute on Drug Abuse Intramural Research Program
Emilya N. Ventriglia: National Institute on Drug Abuse Intramural Research Program
Sherry Lam: National Institute on Drug Abuse Intramural Research Program
Le Wang: University of California San Diego
Ingrid Schoenborn: National Institute on Drug Abuse Intramural Research Program
William Dunne: National Institute on Drug Abuse Intramural Research Program
Michael Michaelides: National Institute on Drug Abuse Intramural Research Program
Scott M. Sternson: Howard Hughes Medical Institute; Janelia Research Campus

Nature, 2025, vol. 646, issue 8085, 746-753

Abstract: Abstract Chemical feedback is ubiquitous in physiology but is challenging to study without perturbing basal functions. One example is addictive drugs, which elicit a positive-feedback cycle of drug-seeking and ingestion by acting on the brain to increase dopamine signalling1–3. However, interfering with this process by altering basal dopamine also adversely affects learning, movement, attention and wakefulness4. Here, inspired by physiological control systems, we developed a highly selective synthetic physiology approach to interfere with the positive-feedback cycle of addiction by installing a cocaine-dependent opposing signalling process into this body–brain signalling loop. We used protein engineering to create cocaine-gated ion channels that are selective for cocaine over other drugs and endogenous molecules. Expression of an excitatory cocaine-gated channel in the rat lateral habenula, a brain region that is normally inhibited by cocaine, suppressed cocaine self-administration without affecting food motivation. This artificial cocaine-activated chemogenetic process reduced the cocaine-induced extracellular dopamine rise in the nucleus accumbens. Our results show that cocaine chemogenetics is a selective approach for countering drug reinforcement by clamping dopamine release in the presence of cocaine. In the future, chemogenetic receptors could be developed for additional addictive drugs or hormones and metabolites, which would facilitate efforts to probe their neural circuit mechanisms using a synthetic physiology approach. As these chemogenetic ion channels are specific for cocaine over natural rewards, they may also offer a route towards gene therapies for cocaine addiction.

Date: 2025
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DOI: 10.1038/s41586-025-09427-8

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