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Here, we show that voluntary cocaine taking decreased plasma GLP-1 levels in rats and that chemogenetic activation of GLP-1\u2013producing neurons in the nucleus tractus solitarius that project to the ventral tegmental area (VTA) decreased cocaine seeking. Single-nuclei transcriptomics and FISH studies revealed that GLP-1Rs are expressed primarily on GABA neurons in the VTA. Using in vivo fiber photometry, we found that the efficacy of a systemic GLP-1R agonist to attenuate cocaine seeking was associated with increased activity of VTA GABA neurons and decreased activity of VTA dopamine neurons. Together, these findings suggest that targeting central GLP-1 circuits may be an effective strategy toward reducing cocaine relapse and highlight a functional role of GABAergic GLP-1R\u2013expressing midbrain neurons in drug seeking.<\/jats:p>","DOI":"10.1126\/sciadv.adr5051","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T13:58:46Z","timestamp":1740578326000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":59,"title":["An endogenous GLP-1 circuit engages VTA GABA neurons to regulate mesolimbic dopamine neurons and attenuate cocaine seeking"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7144-4114","authenticated-orcid":true,"given":"Riley","family":"Merkel","sequence":"first","affiliation":[{"name":"Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0002-9893","authenticated-orcid":true,"given":"Nicole S.","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7338-4784","authenticated-orcid":true,"given":"Vanessa","family":"Weir","sequence":"additional","affiliation":[{"name":"Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Vaegelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yafang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5604-8239","authenticated-orcid":true,"given":"Antonia","family":"Caffrey","sequence":"additional","affiliation":[{"name":"Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7192-6327","authenticated-orcid":true,"given":"Matthew T.","family":"Rich","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Brain Health Institute, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9461-1256","authenticated-orcid":true,"given":"Richard C.","family":"Crist","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7796-587X","authenticated-orcid":true,"given":"Benjamin C.","family":"Reiner","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0646-5605","authenticated-orcid":true,"given":"Heath D.","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","first-page":"e22090","article-title":"Trends of cocaine use and manifestations in hospitalized patients: A cross-sectional study","volume":"14","author":"Gangu K.","year":"2022","unstructured":"K. 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