{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T04:38:55Z","timestamp":1793162335665,"version":"4.5.0"},"posted":{"date-parts":[[2024,6,24]]},"group-title":"Neuroscience","reference-count":71,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,6,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Recent studies show that systemic administration of a glucagon-like peptide-1 receptor (GLP-1R) agonist is sufficient to attenuate the reinstatement of cocaine-seeking behavior, an animal model of relapse. However, the neural mechanisms mediating these effects and the role of endogenous central GLP-1 signaling in cocaine seeking remain unknown. Here, we show that voluntary cocaine taking decreased plasma GLP-1 levels in rats and that chemogenetic activation of GLP-1-producing neurons in the nucleus tractus solitarius (NTS) that project to the ventral tegmental area (VTA) decreased cocaine reinstatement. Single nuclei transcriptomics and FISH studies revealed GLP-1Rs are expressed primarily on GABA neurons in the VTA. Using\n                  <jats:italic>in vivo<\/jats:italic>\n                  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 novel functional role of GABAergic GLP-1R-expressing midbrain neurons in drug seeking.\n                <\/jats:p>","DOI":"10.1101\/2024.06.20.599574","type":"posted-content","created":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T19:40:29Z","timestamp":1719258029000},"source":"Crossref","is-referenced-by-count":9,"title":["An endogenous GLP-1 circuit engages VTA GABA neurons to regulate mesolimbic dopamine neurons and attenuate cocaine seeking"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7144-4114","authenticated-orcid":false,"given":"Riley","family":"Merkel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Hernandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Weir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yafang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew T.","family":"Rich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard C.","family":"Crist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin C.","family":"Reiner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heath D.","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2024062607400978000_2024.06.20.599574v1.1","first-page":"e22090","article-title":"Trends of Cocaine Use and Manifestations in Hospitalized Patients: A Cross-Sectional Study","volume":"14","year":"2022","journal-title":"Cureus"},{"key":"2024062607400978000_2024.06.20.599574v1.2","doi-asserted-by":"crossref","first-page":"940","DOI":"10.15585\/mmwr.mm7129e2","article-title":"Vital Signs: Drug Overdose Deaths, by Selected Sociodemographic and Social Determinants of Health Characteristics - 25 States and the District of Columbia, 2019-2020","volume":"71","year":"2022","journal-title":"MMWR Morb Mortal Wkly Rep"},{"key":"2024062607400978000_2024.06.20.599574v1.3","doi-asserted-by":"crossref","unstructured":"Swinford-Jackson SE , O\u2019Brien CP , Kenny PJ , Vanderschuren L , Unterwald EM , Pierce RC . The Persistent Challenge of Developing Addiction Pharmacotherapies. Cold Spring Harb Perspect Med 11, (2021).","DOI":"10.1101\/cshperspect.a040311"},{"key":"2024062607400978000_2024.06.20.599574v1.4","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.cobeha.2016.02.005","article-title":"GLP-1 influences food and drug reward","volume":"9","year":"2016","journal-title":"Curr Opin Behav Sci"},{"key":"2024062607400978000_2024.06.20.599574v1.5","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.physbeh.2019.03.026","article-title":"Central GLP-1 receptors: Novel molecular targets for cocaine use disorder","volume":"206","year":"2019","journal-title":"Physiol Behav"},{"key":"2024062607400978000_2024.06.20.599574v1.6","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1016\/j.neubiorev.2021.10.026","article-title":"A novel approach to treating opioid use disorders: Dual agonists of glucagon-like peptide-1 receptors and neuropeptide Y(2) receptors","volume":"131","year":"2021","journal-title":"Neurosci Biobehav Rev"},{"key":"2024062607400978000_2024.06.20.599574v1.7","doi-asserted-by":"crossref","first-page":"1063033","DOI":"10.3389\/fphar.2023.1063033","article-title":"The therapeutic potential of glucagon-like peptide-1 for persons with addictions based on findings from preclinical and clinical studies","volume":"14","year":"2023","journal-title":"Front Pharmacol"},{"key":"2024062607400978000_2024.06.20.599574v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-018-0010-3"},{"key":"2024062607400978000_2024.06.20.599574v1.9","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9861(19990111)403:2<261::AID-CNE8>3.0.CO;2-5"},{"key":"2024062607400978000_2024.06.20.599574v1.10","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s00429-020-02189-1","article-title":"Distribution and ultrastructural localization of the glucagon-like peptide-1 receptor (GLP-1R) in the rat brain","volume":"226","year":"2021","journal-title":"Brain Struct Funct"},{"key":"2024062607400978000_2024.06.20.599574v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2010.03.059"},{"key":"2024062607400978000_2024.06.20.599574v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.06.015"},{"key":"2024062607400978000_2024.06.20.599574v1.13","doi-asserted-by":"crossref","unstructured":"Fortin SM , et al. GABA neurons in the nucleus tractus solitarius express GLP-1 receptors and mediate anorectic effects of liraglutide in rats. Sci Transl Med 12, (2020).","DOI":"10.1126\/scitranslmed.aay8071"},{"key":"2024062607400978000_2024.06.20.599574v1.14","doi-asserted-by":"crossref","first-page":"4394","DOI":"10.1038\/s41380-020-00957-3","article-title":"GLP-1 receptor signaling in the laterodorsal tegmental nucleus attenuates cocaine seeking by activating GABAergic circuits that project to the VTA","volume":"26","year":"2021","journal-title":"Mol Psychiatry"},{"key":"2024062607400978000_2024.06.20.599574v1.15","doi-asserted-by":"crossref","unstructured":"Geisler CE , et al. Amylin Modulates a Ventral Tegmental Area-to-Medial Prefrontal Cortex Circuit to Suppress Food Intake and Impulsive Food-Directed Behavior. Biol Psychiatry, (2023).","DOI":"10.1016\/j.biopsych.2023.07.011"},{"key":"2024062607400978000_2024.06.20.599574v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2516"},{"key":"2024062607400978000_2024.06.20.599574v1.17","doi-asserted-by":"crossref","unstructured":"Fortin SM , Chen JC , Petticord MC , Ragozzino FJ , Peters JH , Hayes MR . The locus coeruleus contributes to the anorectic, nausea, and autonomic physiological effects of glucagon-like peptide-1. Sci Adv 9, eadh0980 (2023).","DOI":"10.1126\/sciadv.adh0980"},{"key":"2024062607400978000_2024.06.20.599574v1.18","doi-asserted-by":"publisher","DOI":"10.1111\/adb.12583"},{"key":"2024062607400978000_2024.06.20.599574v1.19","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/s41386-019-0531-4","article-title":"Activation of GLP-1 receptors attenuates oxycodone taking and seeking without compromising the antinociceptive effects of oxycodone in rats","volume":"45","year":"2020","journal-title":"Neuropsychopharmacology"},{"key":"2024062607400978000_2024.06.20.599574v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2011.12.022"},{"key":"2024062607400978000_2024.06.20.599574v1.21","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3579-15.2016"},{"key":"2024062607400978000_2024.06.20.599574v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2015.362"},{"key":"2024062607400978000_2024.06.20.599574v1.23","unstructured":"Paxinos C , Watson G . The rat brain in stereotaxic coordinates. Academic Press (1997)."},{"key":"2024062607400978000_2024.06.20.599574v1.24","doi-asserted-by":"crossref","first-page":"1878","DOI":"10.1038\/s41386-023-01634-z","article-title":"Calcitonin receptor signaling in nucleus accumbens D1R- and D2R-expressing medium spiny neurons bidirectionally alters opioid taking in male rats","volume":"48","year":"2023","journal-title":"Neuropsychopharmacology"},{"key":"2024062607400978000_2024.06.20.599574v1.25","doi-asserted-by":"crossref","first-page":"101422","DOI":"10.1016\/j.molmet.2021.101422","article-title":"Single nuclei RNA sequencing of the rat AP and NTS following GDF15 treatment","volume":"56","year":"2022","journal-title":"Mol Metab"},{"key":"2024062607400978000_2024.06.20.599574v1.26","doi-asserted-by":"publisher","DOI":"10.2337\/db21-0459"},{"key":"2024062607400978000_2024.06.20.599574v1.27","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1038\/s41398-022-02135-1","article-title":"Single nucleus transcriptomic analysis of rat nucleus accumbens reveals cell type-specific patterns of gene expression associated with volitional morphine intake","volume":"12","year":"2022","journal-title":"Transl Psychiatry"},{"key":"2024062607400978000_2024.06.20.599574v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.06.062"},{"key":"2024062607400978000_2024.06.20.599574v1.29","doi-asserted-by":"crossref","first-page":"403","DOI":"10.2147\/DMSO.S141235","article-title":"Reasons for discontinuation of GLP1 receptor agonists: data from a real-world cross-sectional survey of physicians and their patients with type 2 diabetes","volume":"10","year":"2017","journal-title":"Diabetes Metab Syndr Obes"},{"key":"2024062607400978000_2024.06.20.599574v1.30","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1038\/oby.2011.50","article-title":"Comparative effects of the long-acting GLP-1 receptor ligands, liraglutide and exendin-4, on food intake and body weight suppression in rats","volume":"19","year":"2011","journal-title":"Obesity"},{"key":"2024062607400978000_2024.06.20.599574v1.31","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan2475"},{"key":"2024062607400978000_2024.06.20.599574v1.32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0069010"},{"key":"2024062607400978000_2024.06.20.599574v1.33","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2005.04524.x"},{"key":"2024062607400978000_2024.06.20.599574v1.34","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5277-07.2008"},{"key":"2024062607400978000_2024.06.20.599574v1.35","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.drugalcdep.2017.07.033","article-title":"Acute effects of intravenous cocaine administration on serum concentrations of ghrelin, amylin, glucagon-like peptide-1, insulin, leptin and peptide YY and relationships with cardiorespiratory and subjective responses","volume":"180","year":"2017","journal-title":"Drug Alcohol Depend"},{"key":"2024062607400978000_2024.06.20.599574v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.physbeh.2015.06.013"},{"key":"2024062607400978000_2024.06.20.599574v1.37","doi-asserted-by":"publisher","DOI":"10.1210\/en.2011-1443"},{"key":"2024062607400978000_2024.06.20.599574v1.38","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/S0140-6736(18)31773-2","article-title":"Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial","volume":"392","year":"2018","journal-title":"Lancet"},{"key":"2024062607400978000_2024.06.20.599574v1.39","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/ijo.2013.149","article-title":"Tolerability of nausea and vomiting and associations with weight loss in a randomized trial of liraglutide in obese, non-diabetic adults","volume":"38","year":"2014","journal-title":"Int J Obes (Lond"},{"key":"2024062607400978000_2024.06.20.599574v1.40","doi-asserted-by":"publisher","DOI":"10.1007\/s00429-014-0841-6"},{"key":"2024062607400978000_2024.06.20.599574v1.41","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s13041-021-00751-4","article-title":"Long-range GABAergic projections from the nucleus of the solitary tract","volume":"14","year":"2021","journal-title":"Mol Brain"},{"key":"2024062607400978000_2024.06.20.599574v1.42","doi-asserted-by":"crossref","unstructured":"Qiu W , et al. Multiple NTS neuron populations cumulatively suppress food intake. Elife 12, (2023).","DOI":"10.7554\/eLife.85640"},{"key":"2024062607400978000_2024.06.20.599574v1.43","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2742-12.2013"},{"key":"2024062607400978000_2024.06.20.599574v1.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2020.07.084"},{"key":"2024062607400978000_2024.06.20.599574v1.45","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00413.2013"},{"key":"2024062607400978000_2024.06.20.599574v1.46","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6326-11.2012"},{"key":"2024062607400978000_2024.06.20.599574v1.47","doi-asserted-by":"publisher","DOI":"10.1002\/cne.24905"},{"key":"2024062607400978000_2024.06.20.599574v1.48","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1016\/j.molmet.2015.07.008","article-title":"Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain","volume":"4","year":"2015","journal-title":"Mol Metab"},{"key":"2024062607400978000_2024.06.20.599574v1.49","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00034.2006"},{"key":"2024062607400978000_2024.06.20.599574v1.50","doi-asserted-by":"publisher","DOI":"10.1172\/JCI97233"},{"key":"2024062607400978000_2024.06.20.599574v1.51","doi-asserted-by":"publisher","DOI":"10.2337\/db14-0668"},{"key":"2024062607400978000_2024.06.20.599574v1.52","doi-asserted-by":"crossref","unstructured":"Chuong V , et al. The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission. JCI Insight 8, (2023).","DOI":"10.1172\/jci.insight.170671"},{"key":"2024062607400978000_2024.06.20.599574v1.53","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2016.00214"},{"key":"2024062607400978000_2024.06.20.599574v1.54","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-21-08655.2001"},{"key":"2024062607400978000_2024.06.20.599574v1.55","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2004.03232.x"},{"key":"2024062607400978000_2024.06.20.599574v1.56","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4177-03.2004"},{"key":"2024062607400978000_2024.06.20.599574v1.57","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1002\/biof.1406","article-title":"Presynaptic GLP-1 receptors enhance the depolarization-evoked release of glutamate and GABA in the mouse cortex and hippocampus","volume":"44","year":"2018","journal-title":"Biofactors"},{"key":"2024062607400978000_2024.06.20.599574v1.58","doi-asserted-by":"publisher","DOI":"10.1111\/adb.12826"},{"key":"2024062607400978000_2024.06.20.599574v1.59","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0537-18.2018"},{"key":"2024062607400978000_2024.06.20.599574v1.60","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3422-13.2015"},{"key":"2024062607400978000_2024.06.20.599574v1.61","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2011.339"},{"key":"2024062607400978000_2024.06.20.599574v1.62","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1703-16.2016"},{"key":"2024062607400978000_2024.06.20.599574v1.63","doi-asserted-by":"publisher","DOI":"10.1016\/j.physbeh.2017.03.019"},{"key":"2024062607400978000_2024.06.20.599574v1.64","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.13879"},{"key":"2024062607400978000_2024.06.20.599574v1.65","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4570-11.2011"},{"key":"2024062607400978000_2024.06.20.599574v1.66","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.02.015"},{"key":"2024062607400978000_2024.06.20.599574v1.67","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.02.016"},{"key":"2024062607400978000_2024.06.20.599574v1.68","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2016.165"},{"key":"2024062607400978000_2024.06.20.599574v1.69","doi-asserted-by":"publisher","DOI":"10.1002\/cne.23603"},{"key":"2024062607400978000_2024.06.20.599574v1.70","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1002\/cne.24572","article-title":"Relative contributions and mapping of ventral tegmental area dopamine and GABA neurons by projection target in the rat","volume":"527","year":"2019","journal-title":"J Comp Neurol"},{"key":"2024062607400978000_2024.06.20.599574v1.71","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/s42255-021-00344-4","article-title":"Central and peripheral GLP-1 systems independently suppress eating","volume":"3","year":"2021","journal-title":"Nat Metab"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.06.20.599574","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T06:36:32Z","timestamp":1768458992000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.06.20.599574"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,24]]},"references-count":71,"URL":"https:\/\/doi.org\/10.1101\/2024.06.20.599574","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1126\/sciadv.adr5051","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2024,6,24]]},"subtype":"preprint"}}