{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:41:21Z","timestamp":1789137681499,"version":"build-2803163510"},"reference-count":66,"publisher":"Springer Science and Business Media LLC","issue":"8085","license":[{"start":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T00:00:00Z","timestamp":1756252800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T00:00:00Z","timestamp":1756252800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"published-print":{"date-parts":[[2025,10,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>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<jats:sup>1\u20133<\/jats:sup>. However, interfering with this process by altering basal dopamine also adversely affects learning, movement, attention and wakefulness<jats:sup>4<\/jats:sup>. 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\u2013brain 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.<\/jats:p>","DOI":"10.1038\/s41586-025-09427-8","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T15:02:08Z","timestamp":1756306928000},"page":"746-753","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Cocaine chemogenetics blunts drug-seeking by synthetic physiology"],"prefix":"10.1038","volume":"646","author":[{"given":"Juan L.","family":"Gomez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5640-0116","authenticated-orcid":false,"given":"Christopher J.","family":"Magnus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4745-0151","authenticated-orcid":false,"given":"Jordi","family":"Bonaventura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8285-5891","authenticated-orcid":false,"given":"Oscar","family":"Solis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fallon P.","family":"Curry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4360-1503","authenticated-orcid":false,"given":"Marjorie R.","family":"Levinstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reece C.","family":"Budinich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghan L.","family":"Carlton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilya N.","family":"Ventriglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherry","family":"Lam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Schoenborn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1334-6069","authenticated-orcid":false,"given":"William","family":"Dunne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0398-4917","authenticated-orcid":false,"given":"Michael","family":"Michaelides","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0835-444X","authenticated-orcid":false,"given":"Scott M.","family":"Sternson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,27]]},"reference":[{"key":"9427_CR1","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1146\/annurev-neuro-070815-013920","volume":"39","author":"C L\u00fcscher","year":"2016","unstructured":"L\u00fcscher, C. The emergence of a circuit model for addiction. Annu. Rev. Neurosci. 39, 257\u2013276 (2016).","journal-title":"Annu. Rev. Neurosci."},{"key":"9427_CR2","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1151\/spp05314","volume":"3","author":"EJ Nestler","year":"2005","unstructured":"Nestler, E. J. The neurobiology of cocaine addiction. Science Pract. Perspect. 3, 4\u201310 (2005).","journal-title":"Science Pract. Perspect."},{"key":"9427_CR3","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1016\/S2215-0366(16)00104-8","volume":"3","author":"GF Koob","year":"2016","unstructured":"Koob, G. F. & Volkow, N. D. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry 3, 760\u2013773 (2016).","journal-title":"Lancet Psychiatry"},{"key":"9427_CR4","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/j.neuropharm.2014.04.002","volume":"87","author":"KA Phillips","year":"2014","unstructured":"Phillips, K. A., Epstein, D. H. & Preston, K. L. Psychostimulant addiction treatment. Neuropharmacology 87, 150\u2013160 (2014).","journal-title":"Neuropharmacology"},{"key":"9427_CR5","first-page":"30","volume":"99","author":"RT Jones","year":"1990","unstructured":"Jones, R. T. The pharmacology of cocaine smoking in humans. NIDA Res. Monogr. 99, 30\u201341 (1990).","journal-title":"NIDA Res. Monogr."},{"key":"9427_CR6","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1111\/j.1471-4159.1991.tb11425.x","volume":"56","author":"HT Pan","year":"1991","unstructured":"Pan, H. T., Menacherry, S. & Justice, J. B. Jr. Differences in the pharmacokinetics of cocaine in naive and cocaine-experienced rats. J. Neurochem. 56, 1299\u20131306 (1991).","journal-title":"J. Neurochem."},{"key":"9427_CR7","doi-asserted-by":"publisher","first-page":"1909","DOI":"10.1176\/appi.ajp.160.11.1909","volume":"160","author":"ND Volkow","year":"2003","unstructured":"Volkow, N. D. & Swanson, J. M. Variables that affect the clinical use and abuse of methylphenidate in the treatment of ADHD. Am. J. Psychiatry 160, 1909\u20131918 (2003).","journal-title":"Am. J. Psychiatry"},{"key":"9427_CR8","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1146\/annurev-neuro-071013-014048","volume":"37","author":"SM Sternson","year":"2014","unstructured":"Sternson, S. M. & Roth, B. L. Chemogenetic tools to interrogate brain functions. Annu. Rev. Neurosci. 37, 387\u2013407 (2014).","journal-title":"Annu. Rev. Neurosci."},{"key":"9427_CR9","doi-asserted-by":"publisher","first-page":"E8750","DOI":"10.1073\/pnas.1707822114","volume":"114","author":"J Yu","year":"2017","unstructured":"Yu, J. et al. Nucleus accumbens feedforward inhibition circuit promotes cocaine self-administration. Proc. Natl Acad. Sci. USA 114, E8750\u2013E8759 (2017).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"9427_CR10","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1126\/science.1260776","volume":"347","author":"M Creed","year":"2015","unstructured":"Creed, M., Pascoli, V. J. & L\u00fcscher, C. Addiction therapy. Refining deep brain stimulation to emulate optogenetic treatment of synaptic pathology. Science 347, 659\u2013664 (2015).","journal-title":"Science"},{"key":"9427_CR11","doi-asserted-by":"publisher","first-page":"1292","DOI":"10.1126\/science.1206606","volume":"333","author":"CJ Magnus","year":"2011","unstructured":"Magnus, C. J. et al. Chemical and genetic engineering of selective ion channel-ligand interactions. Science 333, 1292\u20131296 (2011).","journal-title":"Science"},{"key":"9427_CR12","doi-asserted-by":"publisher","unstructured":"Magnus, C. J. et al. Ultrapotent chemogenetics for research and potential clinical applications. Science https:\/\/doi.org\/10.1126\/science.aav5282 (2019).","DOI":"10.1126\/science.aav5282"},{"key":"9427_CR13","doi-asserted-by":"publisher","first-page":"18207","DOI":"10.1073\/pnas.0509024102","volume":"102","author":"T Grutter","year":"2005","unstructured":"Grutter, T. et al. Molecular tuning of fast gating in pentameric ligand-gated ion channels. Proc. Natl Acad. Sci. USA 102, 18207\u201318212 (2005).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"9427_CR14","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1038\/366479a0","volume":"366","author":"JL Eisele","year":"1993","unstructured":"Eisele, J. L. et al. Chimaeric nicotinic-serotonergic receptor combines distinct ligand binding and channel specificities. Nature 366, 479\u2013483 (1993).","journal-title":"Nature"},{"key":"9427_CR15","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.1016\/S0022-3565(24)38263-1","volume":"289","author":"MI Damaj","year":"1999","unstructured":"Damaj, M. I., Slemmer, J. E., Carroll, F. I. & Martin, B. R. Pharmacological characterization of nicotine\u2019s interaction with cocaine and cocaine analogs. J. Pharmacol. Exp. Ther. 289, 1229\u20131236 (1999).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"9427_CR16","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/S0026-895X(24)12146-3","volume":"58","author":"MM Francis","year":"2000","unstructured":"Francis, M. M., Vazquez, R. W., Papke, R. L. & Oswald, R. E. Subtype-selective inhibition of neuronal nicotinic acetylcholine receptors by cocaine is determined by the \u03b14 and \u03b24 subunits. Mol. Pharmacol. 58, 109\u2013119 (2000).","journal-title":"Mol. Pharmacol."},{"key":"9427_CR17","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/s41401-019-0276-y","volume":"41","author":"ZG Ma","year":"2020","unstructured":"Ma, Z. G. et al. Cocaine potently blocks neuronal \u03b13\u03b24 nicotinic acetylcholine receptors in SH-SY5Y cells. Acta Pharmacol. Sin. 41, 163\u2013172 (2020).","journal-title":"Acta Pharmacol. Sin."},{"key":"9427_CR18","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1016\/j.jmb.2007.03.067","volume":"369","author":"SB Hansen","year":"2007","unstructured":"Hansen, S. B. & Taylor, P. Galanthamine and non-competitive inhibitor binding to ACh-binding protein: evidence for a binding site on non-\u03b1-subunit interfaces of heteromeric neuronal nicotinic receptors. J. Mol. Biol. 369, 895\u2013901 (2007).","journal-title":"J. Mol. Biol."},{"key":"9427_CR19","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/S0960-894X(00)00670-3","volume":"11","author":"JE Macor","year":"2001","unstructured":"Macor, J. E. et al. The 5-HT3 antagonist tropisetron (ICS 205-930) is a potent and selective \u03b17 nicotinic receptor partial agonist. Bioorg. Med. Chem. Lett. 11, 319\u2013321 (2001).","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"9427_CR20","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.neulet.2004.12.025","volume":"378","author":"RL Papke","year":"2005","unstructured":"Papke, R. L., Schiff, H. C., Jack, B. A. & Horenstein, N. A. Molecular dissection of tropisetron, an \u03b17 nicotinic acetylcholine receptor-selective partial agonist. Neurosci. Lett. 378, 140\u2013144 (2005).","journal-title":"Neurosci. Lett."},{"key":"9427_CR21","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1038\/s41422-021-00509-6","volume":"31","author":"Y Zhao","year":"2021","unstructured":"Zhao, Y. et al. Structural basis of human \u03b17 nicotinic acetylcholine receptor activation. Cell Res. 31, 713\u2013716 (2021).","journal-title":"Cell Res."},{"key":"9427_CR22","doi-asserted-by":"publisher","first-page":"12088","DOI":"10.1073\/pnas.95.21.12088","volume":"95","author":"W Zhong","year":"1998","unstructured":"Zhong, W. et al. From ab initio quantum mechanics to molecular neurobiology: a cation-pi binding site in the nicotinic receptor. Proc. Natl Acad. Sci. USA 95, 12088\u201312093 (1998).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"9427_CR23","doi-asserted-by":"publisher","first-page":"10262","DOI":"10.1021\/bi020266d","volume":"41","author":"DL Beene","year":"2002","unstructured":"Beene, D. L. et al. Cation-pi interactions in ligand recognition by serotonergic (5-HT3A) and nicotinic acetylcholine receptors: the anomalous binding properties of nicotine. Biochemistry 41, 10262\u201310269 (2002).","journal-title":"Biochemistry"},{"key":"9427_CR24","doi-asserted-by":"publisher","first-page":"1990","DOI":"10.1093\/emboj\/cdg197","volume":"22","author":"T Grutter","year":"2003","unstructured":"Grutter, T. et al. An H-bond between two residues from different loops of the acetylcholine binding site contributes to the activation mechanism of nicotinic receptors. EMBO J. 22, 1990\u20132003 (2003).","journal-title":"EMBO J."},{"key":"9427_CR25","doi-asserted-by":"publisher","first-page":"2741","DOI":"10.1038\/npp.2011.165","volume":"36","author":"BA Zimmer","year":"2011","unstructured":"Zimmer, B. A., Dobrin, C. V. & Roberts, D. C. Brain-cocaine concentrations determine the dose self-administered by rats on a novel behaviorally dependent dosing schedule. Neuropsychopharmacology 36, 2741\u20132749 (2011).","journal-title":"Neuropsychopharmacology"},{"key":"9427_CR26","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.neuron.2007.08.025","volume":"56","author":"V Parikh","year":"2007","unstructured":"Parikh, V., Kozak, R., Martinez, V. & Sarter, M. Prefrontal acetylcholine release controls cue detection on multiple timescales. Neuron 56, 141\u2013154 (2007).","journal-title":"Neuron"},{"key":"9427_CR27","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1258\/acb.2009.008191","volume":"47","author":"CA Griffith","year":"2010","unstructured":"Griffith, C. A., Owen, L. J., Body, R., McDowell, G. & Keevil, B. G. Development of a method to measure plasma and whole blood choline by liquid chromatography tandem mass spectrometry. Ann. Clin. Biochem. 47, 56\u201361 (2010).","journal-title":"Ann. Clin. Biochem."},{"key":"9427_CR28","doi-asserted-by":"publisher","first-page":"672","DOI":"10.2967\/jnumed.113.132068","volume":"55","author":"AG Horti","year":"2014","unstructured":"Horti, A. G. et al. 18F-ASEM, a radiolabeled antagonist for imaging the alpha7-nicotinic acetylcholine receptor with PET. J. Nucl. Med. 55, 672\u2013677 (2014).","journal-title":"J. Nucl. Med."},{"key":"9427_CR29","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/1471-2210-6-6","volume":"6","author":"DD Han","year":"2006","unstructured":"Han, D. D. & Gu, H. H. Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs. BMC Pharmacol. 6, 6 (2006).","journal-title":"BMC Pharmacol."},{"key":"9427_CR30","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1126\/science.1948035","volume":"254","author":"JE Kilty","year":"1991","unstructured":"Kilty, J. E., Lorang, D. & Amara, S. G. Cloning and expression of a cocaine-sensitive rat dopamine transporter. Science 254, 578\u2013579 (1991).","journal-title":"Science"},{"key":"9427_CR31","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/0165-6147(93)90029-J","volume":"14","author":"B Giros","year":"1993","unstructured":"Giros, B. & Caron, M. G. Molecular characterization of the dopamine transporter. Trends Pharmacol. Sci. 14, 43\u201349 (1993).","journal-title":"Trends Pharmacol. Sci."},{"key":"9427_CR32","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1146\/annurev.psych.59.103006.093548","volume":"59","author":"GF Koob","year":"2008","unstructured":"Koob, G. F. & Le Moal, M. Addiction and the brain antireward system. Annu. Rev. Psychol. 59, 29\u201353 (2008).","journal-title":"Annu. Rev. Psychol."},{"key":"9427_CR33","doi-asserted-by":"publisher","first-page":"113968","DOI":"10.1016\/j.celrep.2024.113968","volume":"43","author":"D Groos","year":"2024","unstructured":"Groos, D. & Helmchen, F. The lateral habenula: a hub for value-guided behavior. Cell Rep. 43, 113968 (2024).","journal-title":"Cell Rep."},{"key":"9427_CR34","doi-asserted-by":"publisher","first-page":"7501","DOI":"10.1523\/JNEUROSCI.3634-12.2013","volume":"33","author":"TC Jhou","year":"2013","unstructured":"Jhou, T. C. et al. Cocaine drives aversive conditioning via delayed activation of dopamine-responsive habenular and midbrain pathways. J. Neurosci. 33, 7501 (2013).","journal-title":"J. Neurosci."},{"key":"9427_CR35","doi-asserted-by":"publisher","first-page":"e12865","DOI":"10.1111\/adb.12865","volume":"26","author":"SG Nair","year":"2021","unstructured":"Nair, S. G. et al. Effect of chemogenetic inhibition of lateral habenula neuronal activity on cocaine- and food-seeking behaviors in the rat. Addict. Biol. 26, e12865 (2021).","journal-title":"Addict. Biol."},{"key":"9427_CR36","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1016\/S0091-3057(99)00109-4","volume":"64","author":"A Ettenberg","year":"1999","unstructured":"Ettenberg, A., Raven, M. A., Danluck, D. A. & Necessary, B. D. Evidence for opponent-process actions of intravenous cocaine. Pharmacol. Biochem. Behav. 64, 507\u2013512 (1999).","journal-title":"Pharmacol. Biochem. Behav."},{"key":"9427_CR37","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1016\/j.neubiorev.2010.10.012","volume":"35","author":"EC O\u2019Connor","year":"2011","unstructured":"O\u2019Connor, E. C., Chapman, K., Butler, P. & Mead, A. N. The predictive validity of the rat self-administration model for abuse liability. Neurosci. Biobehav. Rev. 35, 912\u2013938 (2011).","journal-title":"Neurosci. Biobehav. Rev."},{"key":"9427_CR38","doi-asserted-by":"publisher","first-page":"S14","DOI":"10.1016\/j.drugalcdep.2009.04.003","volume":"105","author":"LP Carter","year":"2009","unstructured":"Carter, L. P. & Griffiths, R. R. Principles of laboratory assessment of drug abuse liability and implications for clinical development. Drug Alcohol Depend. 105, S14\u2013S25 (2009).","journal-title":"Drug Alcohol Depend."},{"key":"9427_CR39","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/0893-133X(95)00274-H","volume":"14","author":"NK Mello","year":"1996","unstructured":"Mello, N. K. & Negus, S. S. Preclinical evaluation of pharmacotherapies for treatment of cocaine and opioid abuse using drug self-administration procedures. Neuropsychopharmacology 14, 375\u2013424 (1996).","journal-title":"Neuropsychopharmacology"},{"key":"9427_CR40","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/j.neuroscience.2010.03.050","volume":"168","author":"K Brinschwitz","year":"2010","unstructured":"Brinschwitz, K. et al. Glutamatergic axons from the lateral habenula mainly terminate on GABAergic neurons of the ventral midbrain. Neuroscience 168, 463\u2013476 (2010).","journal-title":"Neuroscience"},{"key":"9427_CR41","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1016\/j.neuron.2009.02.001","volume":"61","author":"TC Jhou","year":"2009","unstructured":"Jhou, T. C., Fields, H. L., Baxter, M. G., Saper, C. B. & Holland, P. C. The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses. Neuron 61, 786\u2013800 (2009).","journal-title":"Neuron"},{"key":"9427_CR42","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1523\/JNEUROSCI.06-03-00613.1986","volume":"6","author":"GR Christoph","year":"1986","unstructured":"Christoph, G. R., Leonzio, R. J. & Wilcox, K. S. Stimulation of the lateral habenula inhibits dopamine-containing neurons in the substantia nigra and ventral tegmental area of the rat. J. Neurosci. 6, 613\u2013619 (1986).","journal-title":"J. Neurosci."},{"key":"9427_CR43","doi-asserted-by":"publisher","first-page":"6923","DOI":"10.1523\/JNEUROSCI.0958-07.2007","volume":"27","author":"H Ji","year":"2007","unstructured":"Ji, H. & Shepard, P. D. Lateral habenula stimulation inhibits rat midbrain dopamine neurons through a GABAA receptor-mediated mechanism. J. Neurosci. 27, 6923\u20136930 (2007).","journal-title":"J. Neurosci."},{"key":"9427_CR44","doi-asserted-by":"publisher","first-page":"1755","DOI":"10.1111\/j.1460-9568.2008.06130.x","volume":"27","author":"L Lecourtier","year":"2008","unstructured":"Lecourtier, L., Defrancesco, A. & Moghaddam, B. Differential tonic influence of lateral habenula on prefrontal cortex and nucleus accumbens dopamine release. Eur. J. Neurosci. 27, 1755\u20131762 (2008).","journal-title":"Eur. J. Neurosci."},{"key":"9427_CR45","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1016\/0006-8993(86)90347-1","volume":"373","author":"T Nishikawa","year":"1986","unstructured":"Nishikawa, T., Fage, D. & Scatton, B. Evidence for, and nature of, the tonic inhibitory influence of habenulointerpeduncular pathways upon cerebral dopaminergic transmission in the rat. Brain Res. 373, 324\u2013336 (1986).","journal-title":"Brain Res."},{"key":"9427_CR46","doi-asserted-by":"publisher","first-page":"6704","DOI":"10.1038\/s41380-021-01093-2","volume":"26","author":"J Bonaventura","year":"2021","unstructured":"Bonaventura, J. et al. Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability. Mol. Psychiatry 26, 6704\u20136722 (2021).","journal-title":"Mol. Psychiatry"},{"key":"9427_CR47","doi-asserted-by":"publisher","first-page":"1780","DOI":"10.1038\/npp.2013.77","volume":"38","author":"A Fotros","year":"2013","unstructured":"Fotros, A. et al. Cocaine cue-induced dopamine release in amygdala and hippocampus: a high-resolution PET [18F]fallypride Study in cocaine dependent participants. Neuropsychopharmacology 38, 1780\u20131788 (2013).","journal-title":"Neuropsychopharmacology"},{"key":"9427_CR48","doi-asserted-by":"publisher","first-page":"1156","DOI":"10.1038\/s41592-020-00981-9","volume":"17","author":"F Sun","year":"2020","unstructured":"Sun, F. et al. Next-generation GRAB sensors for monitoring dopaminergic activity in vivo. Nat. Methods 17, 1156\u20131166 (2020).","journal-title":"Nat. Methods"},{"key":"9427_CR49","doi-asserted-by":"publisher","first-page":"e80747","DOI":"10.7554\/eLife.80747","volume":"11","author":"X Liu","year":"2022","unstructured":"Liu, X. et al. Epac2 in midbrain dopamine neurons contributes to cocaine reinforcement via enhancement of dopamine release. eLife 11, e80747 (2022).","journal-title":"eLife"},{"key":"9427_CR50","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.1038\/nature05860","volume":"447","author":"M Matsumoto","year":"2007","unstructured":"Matsumoto, M. & Hikosaka, O. Lateral habenula as a source of negative reward signals in dopamine neurons. Nature 447, 1111\u20131115 (2007).","journal-title":"Nature"},{"key":"9427_CR51","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1523\/JNEUROSCI.1202-15.2016","volume":"36","author":"AM Stamatakis","year":"2016","unstructured":"Stamatakis, A. M. et al. Lateral hypothalamic area glutamatergic neurons and their projections to the lateral habenula regulate feeding and reward. J. Neurosci. 36, 302\u2013311 (2016).","journal-title":"J. Neurosci."},{"key":"9427_CR52","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1038\/nn.3145","volume":"15","author":"AM Stamatakis","year":"2012","unstructured":"Stamatakis, A. M. & Stuber, G. D. Activation of lateral habenula inputs to the ventral midbrain promotes behavioral avoidance. Nat. Neurosci. 15, 1105\u20131107 (2012).","journal-title":"Nat. Neurosci."},{"key":"9427_CR53","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1038\/nature25509","volume":"554","author":"Y Yang","year":"2018","unstructured":"Yang, Y. et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature 554, 317\u2013322 (2018).","journal-title":"Nature"},{"key":"9427_CR54","doi-asserted-by":"publisher","first-page":"1495","DOI":"10.1038\/npp.2013.48","volume":"38","author":"U Beierholm","year":"2013","unstructured":"Beierholm, U. et al. Dopamine modulates reward-related vigor. Neuropsychopharmacology 38, 1495\u20131503 (2013).","journal-title":"Neuropsychopharmacology"},{"key":"9427_CR55","doi-asserted-by":"crossref","unstructured":"Panigrahi, B. et al. Dopamine is required for the neural representation and control of movement vigor. Cell 162, 1418\u20131430 (2015).","DOI":"10.1016\/j.cell.2015.08.014"},{"key":"9427_CR56","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1038\/nn.4173","volume":"19","author":"AA Hamid","year":"2016","unstructured":"Hamid, A. A. et al. Mesolimbic dopamine signals the value of work. Nat. Neurosci. 19, 117\u2013126 (2016).","journal-title":"Nat. Neurosci."},{"key":"9427_CR57","doi-asserted-by":"publisher","first-page":"7025","DOI":"10.1523\/JNEUROSCI.1954-08.2008","volume":"28","author":"D Atasoy","year":"2008","unstructured":"Atasoy, D., Aponte, Y., Su, H. H. & Sternson, S. M. A FLEX switch targets channelrhodopsin-2 to multiple cell types for imaging and long-range circuit mapping. J. Neurosci. 28, 7025\u20137030 (2008).","journal-title":"J. Neurosci."},{"key":"9427_CR58","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/S0165-0270(96)00136-7","volume":"71","author":"GJ Brewer","year":"1997","unstructured":"Brewer, G. J. Isolation and culture of adult rat hippocampal neurons. J. Neurosci. Methods 71, 143\u2013155 (1997).","journal-title":"J. Neurosci. Methods"},{"key":"9427_CR59","first-page":"100","volume":"4","author":"BA Suter","year":"2010","unstructured":"Suter, B. A. et al. Ephus: multipurpose data acquisition software for neuroscience experiments. Front. Neural Circ. 4, 100 (2010).","journal-title":"Front. Neural Circ."},{"key":"9427_CR60","doi-asserted-by":"crossref","unstructured":"Mukherjee, J. et al. Dopamine D3 receptor binding of 18F-fallypride: evaluation using in vitro and in vivo PET imaging studies. Synapse 69, 577\u2013591 (2015).","DOI":"10.1002\/syn.21867"},{"key":"9427_CR61","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.2967\/jnumed.111.099416","volume":"53","author":"J Ceccarini","year":"2012","unstructured":"Ceccarini, J. et al. Optimized in vivo detection of dopamine release using 18F-fallypride PET. J. Nucl. Med. 53, 1565\u20131572 (2012).","journal-title":"J. Nucl. Med."},{"key":"9427_CR62","doi-asserted-by":"publisher","first-page":"eadd1014","DOI":"10.1126\/scitranslmed.add1014","volume":"15","author":"J Bonaventura","year":"2023","unstructured":"Bonaventura, J. et al. Expression of the excitatory opsin ChRER\u03b1 can be traced longitudinally in rat and nonhuman primate brains with PET imaging. Sci. Transl. Med. 15, eadd1014 (2023).","journal-title":"Sci. Transl. Med."},{"key":"9427_CR63","doi-asserted-by":"publisher","first-page":"3351","DOI":"10.1016\/j.celrep.2018.02.081","volume":"22","author":"SL Jackman","year":"2018","unstructured":"Jackman, S. L. et al. Silk fibroin films facilitate single-step targeted expression of optogenetic proteins. Cell Rep. 22, 3351\u20133361 (2018).","journal-title":"Cell Rep."},{"key":"9427_CR64","doi-asserted-by":"publisher","first-page":"173093","DOI":"10.1016\/j.pbb.2020.173093","volume":"201","author":"CA Bruno","year":"2021","unstructured":"Bruno, C. A. et al. pMAT: An open-source software suite for the analysis of fiber photometry data. Pharmacol. Biochem. Behav. 201, 173093 (2021).","journal-title":"Pharmacol. Biochem. Behav."},{"key":"9427_CR65","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-03626-9","volume":"11","author":"VN Sherathiya","year":"2021","unstructured":"Sherathiya, V. N., Schaid, M. D., Seiler, J. L., Lopez, G. C. & Lerner, T. N. GuPPy, a Python toolbox for the analysis of fiber photometry data. Sci. Rep. 11, 24212 (2021).","journal-title":"Sci. Rep."},{"key":"9427_CR66","doi-asserted-by":"publisher","unstructured":"Solis, O. Gomez et al\/F-Phot-Analysis: v1.0.0 initial release \u2013 F-Phot-Analysis. Zenodo https:\/\/doi.org\/10.5281\/zenodo.15665589 (2025).","DOI":"10.5281\/zenodo.15665589"}],"container-title":["Nature"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41586-025-09427-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-025-09427-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-025-09427-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T17:02:30Z","timestamp":1760547750000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41586-025-09427-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,27]]},"references-count":66,"journal-issue":{"issue":"8085","published-print":{"date-parts":[[2025,10,16]]}},"alternative-id":["9427"],"URL":"https:\/\/doi.org\/10.1038\/s41586-025-09427-8","relation":{},"ISSN":["0028-0836","1476-4687"],"issn-type":[{"value":"0028-0836","type":"print"},{"value":"1476-4687","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,27]]},"assertion":[{"value":"13 May 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 July 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 August 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"S.M.S. and C.J.M. have a pending patent application on this technology (US patent application 20240002463-A1) as well as additional issued patents on related chemogenetic technologies. S.M.S. is a consultant for Kriya Therapeutics, which is focused on therapeutic applications of chemogenetics. M.M. is a principal investigator on a cooperative research and development agreement between NIDA and Kriya Therapeutics. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}