{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:16:45Z","timestamp":1785421005874,"version":"3.56.0"},"posted":{"date-parts":[[2026,3,11]]},"group-title":"Neuroscience","reference-count":47,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"award":["ZIA MH002987"],"award-info":[{"award-number":["ZIA MH002987"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["ZIA AA000421"],"award-info":[{"award-number":["ZIA AA000421"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["ZIA DA000069"],"award-info":[{"award-number":["ZIA DA000069"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,11]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  A defining feature of substance use disorder is that repeated drug use does not always lead to addiction, motivating the search for biomarkers of vulnerability\n                  <jats:sup>1<\/jats:sup>\n                  . Reduced striatal dopamine D2\/3 receptor availability is a robust PET correlate of problematic stimulant use\n                  <jats:sup>2\u20135<\/jats:sup>\n                  , but the signal may reflect high endogenous dopamine level, and it conflates presynaptic D2 autoreceptors on dopamine axons with postsynaptic D2\/3 heteroreceptors on striatal projection neurons. We dissociated these contributions using cell type\u2013specific Drd2 haploinsufficiency in dopamine neurons (autoD2KD), D2-expressing medium spiny neurons (MSN-D2KD), or both. Autoreceptor haploinsufficiency (autoD2KD) weakened presynaptic control of dopamine release, enhanced phasic gain, and prolonged cocaine-evoked dopamine elevations. This was accompanied by a hyper-exploratory trait and altered cocaine adaptation. Specifically, autoD2KD mice showed greater cocaine-seeking behavior, despite intact responses to sucrose reward and punishment. Although all genotypes showed graded reductions in striatal D2\/3 binding, D1-like compensations diverged, resulting in different D1:D2\/3 ratio in the striatum. The clinical implication is that striatal D1 density and D1:D2\/3 balance may emerge as critical biomarkers for distinguishing cell-type-specific D2 reductions relevant to addiction vulnerability.\n                <\/jats:p>","DOI":"10.64898\/2026.03.10.710882","type":"posted-content","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T11:45:13Z","timestamp":1773229513000},"source":"Crossref","is-referenced-by-count":0,"title":["D2 autoreceptors gate vulnerability to cocaine use disorder"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4179-7717","authenticated-orcid":false,"given":"Erin M","family":"Murray","sequence":"first","affiliation":[{"name":"NIAAA, National Institutes of Health, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Diaz-Urbina","sequence":"additional","affiliation":[{"name":"NIMH, National Institutes of Health, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Bock","sequence":"additional","affiliation":[{"name":"NIAAA, National Institutes of Health, Bethesda, MD 20892"},{"name":"NIMH, National Institutes of Health, Bethesda, MD 20892"},{"name":"Center on Compulsive Behaviors, National Institutes of Health, Bethesda, MD 208923"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5077-5443","authenticated-orcid":false,"given":"Emilya","family":"Ventriglia","sequence":"additional","affiliation":[{"name":"Center on Compulsive Behaviors, National Institutes of Health, Bethesda, MD 208923"},{"name":"NIDA, National Institutes of Health, Baltimore, MD 21224"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4268-5904","authenticated-orcid":false,"given":"Anna","family":"Tischer","sequence":"additional","affiliation":[{"name":"NIDA, National Institutes of Health, Baltimore, MD 21224"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung Hoon","family":"Shin","sequence":"additional","affiliation":[{"name":"NIAAA, National Institutes of Health, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seul Ah","family":"Lee","sequence":"additional","affiliation":[{"name":"NIMH, National Institutes of Health, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8908-2887","authenticated-orcid":false,"given":"Lucy G","family":"Anderson","sequence":"additional","affiliation":[{"name":"NIMH, National Institutes of Health, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney","family":"Cerveny","sequence":"additional","affiliation":[{"name":"NIMH, National Institutes of Health, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Bleimeister","sequence":"additional","affiliation":[{"name":"NIAAA, National Institutes of Health, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9217-032X","authenticated-orcid":false,"given":"Miriam E","family":"Bocarsly","sequence":"additional","affiliation":[{"name":"NIAAA, National Institutes of Health, Bethesda, MD 20892"},{"name":"Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Rutgers Brain Health Institute. 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