NIDA IRP Technology Resource Initiative Featured Paper

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Cocaine chemogenetics blunts drug-seeking by synthetic physiology.

Published in Nature.

Authors

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, Scott M Sternson

Paper presented by Oscar Solis Castrejon, Ph.d. and selected by the NIDA TDI Paper of the Month Committee

Publication Brief Description

This study introduces a novel chemogenetic approach where cocaine itself acts as a molecular key to activate engineered receptors. This allows for specific closed-loop control of brain circuits during cocaine exposure. It addresses a key limitation in addiction research, which is the lack of tools to modulate drug-induced activity in a selective way. The authors engineered cocaine-gated ion channels that act as specialized switches that only respond when cocaine is present. When expressed in the lateral habenula, a brain region associated with motivation, activation during cocaine exposure reduced cocaine self-administration without affecting natural reward behaviors. This technique of drug-gated chemogenetics offers a highly precise method to study and potentially treat addiction by targeting only the circuits activated by the drug, leaving the rest of the brain’s natural functions untouched.

Gomez, Juan L; Magnus, Christopher J; Bonaventura, Jordi; Solis, Oscar; Curry, Fallon P; Levinstein, Marjorie R; Budinich, Reece C; Carlton, Meghan L; Ventriglia, Emilya N; Lam, Sherry; Wang, Le; Schoenborn, Ingrid; Dunne, William; Michaelides, Michael; Sternson, Scott M

Cocaine chemogenetics blunts drug-seeking by synthetic physiology Journal Article

In: Nature, vol. 646, no. 8085, pp. 746–753, 2025, ISSN: 1476-4687.

Abstract | Links

@article{pmid40866713b,

title = {Cocaine chemogenetics blunts drug-seeking by synthetic physiology},

author = {Juan L Gomez and Christopher J Magnus and Jordi Bonaventura and Oscar Solis and Fallon P Curry and Marjorie R Levinstein and Reece C Budinich and Meghan L Carlton and Emilya N Ventriglia and Sherry Lam and Le Wang and Ingrid Schoenborn and William Dunne and Michael Michaelides and Scott M Sternson},

url = {https://pubmed.ncbi.nlm.nih.gov/40866713/},

doi = {10.1038/s41586-025-09427-8},

issn = {1476-4687},

year  = {2025},

date = {2025-10-01},

urldate = {2025-10-01},

journal = {Nature},

volume = {646},

number = {8085},

pages = {746--753},

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 signalling. However, interfering with this process by altering basal dopamine also adversely affects learning, movement, attention and wakefulness. 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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}