Cocaine chemogenetics blunts drug-seeking by synthetic physiology

Study Author Juan Gomez

Hot Off the Press – March 2026

Published in Nature by Juan Gomez and Michael Michaelides et al. of the NIDA IRP Biobehavioral Imaging and Molecular Neuropsychopharmacology Section.

Summary

Our research team is pleased to announce the publication of our latest study in Nature, introducing a transformative synthetic biology platform designed to study and combat cocaine addiction. We used protein engineering to develop excitatory and inhibitory cocaine-gated ion channels. By targeting an excitatory cocaine-gated channel to the rat lateral habenula, a brain region that is normally inhibited by cocaine, we were able to reduce cocaine intake. We therefore engineered a synthetic “closed-loop” negative feedback system where cocaine itself is the key that engages the engineered cocaine channel to change the normal brain physiological response to cocaine. Traditional pharmacological methods often lack the specificity to distinguish between drug-induced neural activity and natural reward processing. Our system ensures that the biological pathways for pleasure from stimuli such as food or social interaction remain undisturbed, activating only in the presence of the drug of abuse, in this case cocaine. This allows for precise time-locked activation of specific brain regions only when cocaine is available, which helps reduce side-effects associated with systemic treatments or classic chemogenetic neuromodulation. The engineered cocaine-gated ion channels are commercially available from Addgene and our lab would be willing to provide guidance to anyone wishing to utilize this new technology.

Publication Information

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{pmid40866713,

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.},

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pubstate = {published},

tppubtype = {article}

}