{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T15:45:58Z","timestamp":1782575158227,"version":"3.54.5"},"posted":{"date-parts":[[2026,6,24]]},"group-title":"Neuroscience","reference-count":41,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"crossref","award":["R01DA037897"],"award-info":[{"award-number":["R01DA037897"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"crossref","award":["R01DA061799"],"award-info":[{"award-number":["R01DA061799"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"crossref","award":["R21DA057458"],"award-info":[{"award-number":["R21DA057458"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"crossref","award":["R21DA055846"],"award-info":[{"award-number":["R21DA055846"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Cocaine use disorder (CUD) remains a major public health concern with no FDA-approved pharmacotherapy, underscoring the need to define the cellular and molecular adaptations produced by voluntary cocaine taking. The nucleus accumbens (NAc) is a key substrate for cocaine reinforcement and drug-seeking behavior, but interpretation of the functional role of its cellular heterogeneity in these behaviors is limited by past bulk transcriptomic studies. Here, we used single-nucleus RNA sequencing to profile the NAc of male and female rats that self-administered intravenous cocaine for 10 consecutive days versus yoked saline controls. After quality control, we analyzed 36,766 nuclei spanning major neuronal, glial, and vascular cell populations. Pseudobulk differential-expression analyses identified 478 cocaine-associated cell type-specific transcriptional changes that were concentrated in discrete medium spiny neuron (MSN) subclasses and astrocytes. D1\n                  <jats:italic>Ebf1<\/jats:italic>\n                  + MSNs showed the largest transcriptomic response, accounting for \u223c40% of all differential-expression events, followed by D2\n                  <jats:italic>Stk32a<\/jats:italic>\n                  + MSNs, astrocytes, and D1\n                  <jats:italic>Ppm1e<\/jats:italic>\n                  + MSNs. These responses were largely cell type-specific, indicating that cocaine self-administration engages multiple molecular programs rather than a uniform accumbens-wide transcriptional signature. Immediate-early gene module-score analyses further revealed cocaine-associated activation states in select neuronal and non-neuronal cell populations, including D1\n                  <jats:italic>Ebf1<\/jats:italic>\n                  + MSNs, Drd3+ neurons, Sst+ interneurons, astrocytes, and oligodendrocytes. Gene-set, pathway, and upstream-regulator analyses nominated synaptic organization, axon guidance, RAS\/MAPK signaling, NMDA receptor-associated signaling, and CREB-related transcriptional regulation as candidate mechanisms of cocaine-evoked plasticity. Together, these data provide a cell type-resolved resource for understanding how voluntary cocaine taking alters the rat NAc transcriptome and identifies discrete neuronal and glial cell populations for future mechanistic studies using preclinical CUD models.\n                <\/jats:p>","DOI":"10.64898\/2026.06.19.733392","type":"posted-content","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T23:25:11Z","timestamp":1782343511000},"source":"Crossref","is-referenced-by-count":0,"title":["Volitional cocaine taking engages distinct medium spiny neuron and astrocyte transcriptional programs in the rat nucleus accumbens"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0646-5605","authenticated-orcid":false,"given":"Heath D.","family":"Schmidt","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\/0000-0001-9461-1256","authenticated-orcid":false,"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\/0000-0002-0701-9260","authenticated-orcid":false,"given":"Samar N.","family":"Chehimi","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\/0000-0002-7144-4114","authenticated-orcid":false,"given":"Riley","family":"Merkel","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\/0009-0006-4041-4824","authenticated-orcid":false,"given":"Morgan","family":"Faist","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaishnavi","family":"Joshi","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jackson E.","family":"Shuey","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":false,"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"}]}],"member":"54368","reference":[{"key":"2026062707550435000_2026.06.19.733392v1.1","unstructured":"SAMHSA, Key substance use and mental health indicators in the United States: Results from the 2024 National Survey on Drug Use and Health 2024, Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration: Rockville, MD."},{"key":"2026062707550435000_2026.06.19.733392v1.2","doi-asserted-by":"crossref","unstructured":"Garnett, M.F. and A.M. 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