{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T10:40:07Z","timestamp":1773052807121,"version":"3.50.1"},"posted":{"date-parts":[[2024,1,26]]},"group-title":"Neuroscience","reference-count":67,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,1,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces relapse. Vagus nerve stimulation (VNS) has previously been shown to enhance extinction learning and reduce drug-seeking. Here we determined the effects of VNS-mediated release of brain-derived neurotrophic factor (BDNF) on extinction and cue-induced reinstatement in rats trained to self-administer cocaine. Pairing 10 days of extinction training with VNS facilitated extinction and reduced drug-seeking behavior during reinstatement. Rats that received a single extinction session with VNS showed elevated BDNF levels in the medial PFC as determined via an enzyme-linked immunosorbent assay (ELISA). Systemic blockade of Tropomyosin receptor kinase B (TrkB) receptors during extinction, via the TrkB antagonist ANA-12, decreased the effects of VNS on extinction and reinstatement. Whole-cell recordings in brain slices showed that cocaine self-administration induced alterations in the ratio of AMPA and NMDA receptor-mediated currents in layer 5 pyramidal neurons of the infralimbic cortex (IL). Pairing extinction with VNS reversed cocaine-induced changes in glutamatergic transmission by enhancing AMPAR currents, and this effect was blocked by ANA-12. Our study suggests that VNS consolidates extinction of drug-seeking behavior by reversing drug-induced changes in synaptic AMPA receptors in the IL, and this effect is abolished by blocking TrkB receptors during extinction, highlighting a potential mechanism for the therapeutic effects of VNS in addiction.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>Extinction training can reverse maladaptive neuroplasticity induced by drugs of abuse, but adjunct treatments are sought that can facilitate the process and consolidate the newly formed memories. Pairing extinction training with vagus nerve stimulation (VNS) facilitates extinction and reduces drug-seeking behavior during reinstatement. Here, we show that rats receiving a single extinction session with VNS exhibit elevated brain-derived neurotrophic factor (BDNF) levels in the medial prefrontal cortex (mPFC). We also demonstrate that VNS consolidates the extinction of drug-seeking behavior by reversing cocaine-induced changes in synaptic AMPA receptors in the infralimbic cortex (IL) of the mPFC. This effect is blocked by the TrkB antagonist ANA-12, emphasizing the role of BDNF and TrkB receptors in the therapeutic effects of VNS in addiction.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.01.25.577293","type":"posted-content","created":{"date-parts":[[2024,1,26]],"date-time":"2024-01-26T18:50:12Z","timestamp":1706295012000},"source":"Crossref","is-referenced-by-count":2,"title":["Vagus nerve stimulation (VNS) modulates synaptic plasticity in the rat infralimbic cortex via Trk-B receptor activation to reduce drug-seeking"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4914-9876","authenticated-orcid":false,"given":"Christopher M.","family":"Driskill","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4107-5581","authenticated-orcid":false,"given":"Jessica E.","family":"Childs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3784-7654","authenticated-orcid":false,"given":"Aarron J.","family":"Phensy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sierra R.","family":"Rodriguez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John T.","family":"O\u2019Brien","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1213-6664","authenticated-orcid":false,"given":"Kathy L.","family":"Lindquist","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aurian","family":"Naderi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bogdan","family":"Bordieanu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacqueline F.","family":"McGinty","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1728-8111","authenticated-orcid":false,"given":"Sven","family":"Kroener","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024013005300483000_2024.01.25.577293v1.1","doi-asserted-by":"crossref","unstructured":"Amagase, Y. , Kambayashi, R. , Sugiyama, A. , Takei, Y ., 2023. Peripheral Regulation of Central Brain-Derived Neurotrophic Factor Expression through the Vagus Nerve. Int J Mol Sci 24.","DOI":"10.3390\/ijms24043543"},{"key":"2024013005300483000_2024.01.25.577293v1.2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0773-16.2016"},{"key":"2024013005300483000_2024.01.25.577293v1.3","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1038\/npp.2017.114","article-title":"Role of Src Family Kinases in BDNF-Mediated Suppression of Cocaine-Seeking and Prevention of Cocaine-Induced ERK, GluN2A, and GluN2B Dephosphorylation in the Prelimbic Cortex","volume":"42","year":"2017","journal-title":"Neuropsychopharmacology"},{"key":"2024013005300483000_2024.01.25.577293v1.4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1994.tb02482.x"},{"key":"2024013005300483000_2024.01.25.577293v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2006.10.069"},{"key":"2024013005300483000_2024.01.25.577293v1.6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2007.05692.x"},{"key":"2024013005300483000_2024.01.25.577293v1.7","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5457-08.2009"},{"key":"2024013005300483000_2024.01.25.577293v1.8","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.neuroscience.2017.11.004","article-title":"The Interval Between VNS-Tone Pairings Determines the Extent of Cortical Map Plasticity","volume":"369","year":"2018","journal-title":"Neuroscience"},{"key":"2024013005300483000_2024.01.25.577293v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2018.08.006"},{"key":"2024013005300483000_2024.01.25.577293v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/srep35135"},{"key":"2024013005300483000_2024.01.25.577293v1.11","doi-asserted-by":"publisher","DOI":"10.1172\/JCI43992"},{"key":"2024013005300483000_2024.01.25.577293v1.12","first-page":"73","article-title":"Cue reactivity and cue reactivity interventions in drug dependence","volume":"137","year":"1993","journal-title":"NIDA Res Monogr"},{"key":"2024013005300483000_2024.01.25.577293v1.13","doi-asserted-by":"crossref","unstructured":"Childs, J.E. , Alvarez-Dieppa, A.C. , McIntyre, C.K. , Kroener, S ., 2015. Vagus Nerve Stimulation as a Tool to Induce Plasticity in Pathways Relevant for Extinction Learning. J Vis Exp, e 53032.","DOI":"10.3791\/53032"},{"key":"2024013005300483000_2024.01.25.577293v1.14","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1101\/lm.043539.116","article-title":"Vagus nerve stimulation reduces cocaine seeking and alters plasticity in the extinction network","volume":"24","year":"2017","journal-title":"Learn Mem"},{"key":"2024013005300483000_2024.01.25.577293v1.15","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1016\/j.brs.2019.07.001","article-title":"Vagus nerve stimulation during extinction learning reduces conditioned place preference and context-induced reinstatement of cocaine seeking","volume":"12","year":"2019","journal-title":"Brain Stimul"},{"key":"2024013005300483000_2024.01.25.577293v1.16","doi-asserted-by":"publisher","DOI":"10.1006\/nlme.1995.1024"},{"key":"2024013005300483000_2024.01.25.577293v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/4600"},{"key":"2024013005300483000_2024.01.25.577293v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2021.02.049"},{"key":"2024013005300483000_2024.01.25.577293v1.19","doi-asserted-by":"publisher","DOI":"10.1046\/j.1360-0443.2002.00014.x"},{"key":"2024013005300483000_2024.01.25.577293v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00475-X"},{"key":"2024013005300483000_2024.01.25.577293v1.21","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.106.104166"},{"key":"2024013005300483000_2024.01.25.577293v1.22","doi-asserted-by":"publisher","DOI":"10.1007\/BF02245266"},{"key":"2024013005300483000_2024.01.25.577293v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2007.08.045"},{"key":"2024013005300483000_2024.01.25.577293v1.24","doi-asserted-by":"publisher","DOI":"10.1151\/spp07324"},{"key":"2024013005300483000_2024.01.25.577293v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-020-0705-0"},{"key":"2024013005300483000_2024.01.25.577293v1.26","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2007.05918.x"},{"key":"2024013005300483000_2024.01.25.577293v1.27","doi-asserted-by":"publisher","DOI":"10.1017\/S146114571200096X"},{"key":"2024013005300483000_2024.01.25.577293v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.euroneuro.2016.10.002"},{"key":"2024013005300483000_2024.01.25.577293v1.29","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3821-16.2017"},{"key":"2024013005300483000_2024.01.25.577293v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2013.06.026"},{"key":"2024013005300483000_2024.01.25.577293v1.31","doi-asserted-by":"crossref","first-page":"112596","DOI":"10.1016\/j.bbr.2020.112596","article-title":"Facilitative effects of environmental enrichment for cocaine relapse prevention are dependent on extinction training context and involve increased TrkB signaling in dorsal hippocampus and ventromedial prefrontal cortex","volume":"386","year":"2020","journal-title":"Behav Brain Res"},{"key":"2024013005300483000_2024.01.25.577293v1.32","doi-asserted-by":"publisher","DOI":"10.1097\/WNR.0000000000000154"},{"key":"2024013005300483000_2024.01.25.577293v1.33","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2010.05899.x"},{"key":"2024013005300483000_2024.01.25.577293v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2012.59"},{"key":"2024013005300483000_2024.01.25.577293v1.35","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1111\/adb.12689","article-title":"ARC and BDNF expression after cocaine self-administration or cue-induced reinstatement of cocaine seeking in adolescent and adult male rats","volume":"23","year":"2018","journal-title":"Addict Biol"},{"key":"2024013005300483000_2024.01.25.577293v1.36","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2011.07754.x"},{"key":"2024013005300483000_2024.01.25.577293v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2014.11.018"},{"key":"2024013005300483000_2024.01.25.577293v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2011.02.059"},{"key":"2024013005300483000_2024.01.25.577293v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2009.05.038"},{"key":"2024013005300483000_2024.01.25.577293v1.40","doi-asserted-by":"publisher","DOI":"10.1017\/S1461145712000387"},{"key":"2024013005300483000_2024.01.25.577293v1.41","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.jad.2019.11.090","article-title":"Vagus nerve stimulation produces immediate dose-dependent anxiolytic effect in rats","volume":"265","year":"2020","journal-title":"J Affect Disord"},{"key":"2024013005300483000_2024.01.25.577293v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2009.08.078"},{"key":"2024013005300483000_2024.01.25.577293v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2010.10.037"},{"key":"2024013005300483000_2024.01.25.577293v1.44","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-018-4964-y"},{"key":"2024013005300483000_2024.01.25.577293v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2011.01.018"},{"key":"2024013005300483000_2024.01.25.577293v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2011.05.024"},{"key":"2024013005300483000_2024.01.25.577293v1.47","doi-asserted-by":"publisher","DOI":"10.1101\/lm.048447.118"},{"key":"2024013005300483000_2024.01.25.577293v1.48","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.brs.2018.09.013","article-title":"Vagus nerve stimulation promotes generalization of conditioned fear extinction and reduces anxiety in rats","volume":"12","year":"2019","journal-title":"Brain Stimul"},{"key":"2024013005300483000_2024.01.25.577293v1.49","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1016\/j.brs.2022.08.001","article-title":"Vagus nerve stimulation-induced cognitive enhancement: Hippocampal neuroplasticity in healthy male rats","volume":"15","year":"2022","journal-title":"Brain Stimul"},{"key":"2024013005300483000_2024.01.25.577293v1.50","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4980-13.2014"},{"key":"2024013005300483000_2024.01.25.577293v1.51","doi-asserted-by":"crossref","first-page":"2000","DOI":"10.1038\/npp.2017.90","article-title":"Reversal of Cocaine-Associated Synaptic Plasticity in Medial Prefrontal Cortex Parallels Elimination of Memory Retrieval","volume":"42","year":"2017","journal-title":"Neuropsychopharmacology"},{"key":"2024013005300483000_2024.01.25.577293v1.52","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2014.00327"},{"key":"2024013005300483000_2024.01.25.577293v1.53","doi-asserted-by":"publisher","DOI":"10.1101\/lm.1041309"},{"key":"2024013005300483000_2024.01.25.577293v1.54","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.nbd.2016.02.021","article-title":"Prefrontal cortical BDNF: A regulatory key in cocaine- and food-reinforced behaviors","volume":"91","year":"2016","journal-title":"Neurobiol Dis"},{"key":"2024013005300483000_2024.01.25.577293v1.55","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhr316"},{"key":"2024013005300483000_2024.01.25.577293v1.56","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.12422"},{"key":"2024013005300483000_2024.01.25.577293v1.57","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2006.08.048"},{"key":"2024013005300483000_2024.01.25.577293v1.58","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1080\/01677063.2021.1931180","article-title":"Loss of mGluR1-LTD following cocaine exposure accumulates Ca(2+)-permeable AMPA receptors and facilitates synaptic potentiation in the prefrontal cortex","volume":"35","year":"2021","journal-title":"J Neurogenet"},{"key":"2024013005300483000_2024.01.25.577293v1.59","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.neuroscience.2023.09.015","article-title":"Vagus Nerve Stimulation Must Occur During Tactile Rehabilitation to Enhance Somatosensory Recovery","volume":"532","year":"2023","journal-title":"Neuroscience"},{"key":"2024013005300483000_2024.01.25.577293v1.60","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1248\/bpb.b19-00318","article-title":"Acute Cocaine Reduces Excitatory Synaptic Transmission in Pyramidal Neurons of the Mouse Medial Prefrontal Cortex","volume":"42","year":"2019","journal-title":"Biol Pharm Bull"},{"key":"2024013005300483000_2024.01.25.577293v1.61","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-013-3118-5"},{"key":"2024013005300483000_2024.01.25.577293v1.62","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2008.07.027"},{"key":"2024013005300483000_2024.01.25.577293v1.63","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-12178-w"},{"key":"2024013005300483000_2024.01.25.577293v1.64","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2711-14.2016"},{"key":"2024013005300483000_2024.01.25.577293v1.65","doi-asserted-by":"publisher","DOI":"10.1016\/S0893-133X(01)00238-X"},{"key":"2024013005300483000_2024.01.25.577293v1.66","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4986-10.2011"},{"key":"2024013005300483000_2024.01.25.577293v1.67","doi-asserted-by":"crossref","first-page":"168","DOI":"10.3389\/fnbeh.2019.00168","article-title":"Infralimbic Estradiol Enhances Neuronal Excitability and Facilitates Extinction of Cocaine Seeking in Female Rats via a BDNF\/TrkB Mechanism","volume":"13","year":"2019","journal-title":"Front Behav Neurosci"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.01.25.577293","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T05:50:55Z","timestamp":1768456255000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.01.25.577293"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,26]]},"references-count":67,"URL":"https:\/\/doi.org\/10.1101\/2024.01.25.577293","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1523\/JNEUROSCI.0107-24.2024","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2024,1,26]]},"subtype":"preprint"}}