{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T05:53:51Z","timestamp":1788587631568,"version":"build-2803163510"},"posted":{"date-parts":[[2026,3,14]]},"group-title":"Neuroscience","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T00:00:00Z","timestamp":1773446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["F31DA058522"],"award-info":[{"award-number":["F31DA058522"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01DA054329"],"award-info":[{"award-number":["R01DA054329"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Homer Lindsey Bruce & Fred Murphy Jones Endowed Fellowship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Cocaine seeking after abstinence is associated with increased ventral pallidum (VP) activity. This increase appears to involve an opioid peptide that suppresses GABA release from D2 receptor-expressing medium spiny neurons (D2-MSNs) to the VP, but its identity is unclear. We previously found that cocaine abstinence increases enkephalin mRNA expression in D2-MSNs and that exogenous enkephalin inhibits GABA release from these neurons. We therefore hypothesized that cocaine-enhanced enkephalin release from D2-MSNs suppresses GABA release into the VP, which disinhibits VP neurons and promotes cocaine seeking.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    To examine how enkephalin alters striatal circuit plasticity and cocaine seeking following abstinence, we performed\n                    <jats:italic>ex vivo<\/jats:italic>\n                    electrophysiology and cocaine self-administration in mice lacking enkephalin selectively from D2-MSNs (D2-PenkKO). Recordings were obtained from the primary D2-MSNs targets: VP neurons and D1 receptor-expressing MSNs (D1-MSNs).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Following cocaine abstinence, GABA release from D2-MSNs to VP neurons was reduced in controls, but not D2-PenkKOs. In contrast, cocaine abstinence did not alter GABA release to D1-MSNs. Optogenetically evoked GABA release from D2-MSNs inhibited VP neuron firing in saline-abstinent controls and D2-PenkKOs, but not cocaine-abstinent controls. Female, but not male, D2-PenkKOs self-administered less cocaine in early acquisition and exhibited blunted cue-induced cocaine seeking after abstinence.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Abstinence from cocaine self-administration increases D2-MSN enkephalin expression, leading to auto-inhibition of GABA release onto VP neurons, but not D1-MSNs, thereby selectively disinhibiting VP neuron activity. These findings identify enkephalin as a key mediator of cocaine abstinence-induced striatopallidal circuit plasticity and suggest that this plasticity contributes to cocaine seeking following abstinence.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.11.711212","type":"posted-content","created":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T06:10:11Z","timestamp":1773555011000},"source":"Crossref","is-referenced-by-count":1,"title":["Cocaine-Enhanced Enkephalin Gates Plasticity of Distinct Striatal Synapses and Facilitates Cue-Induced Cocaine-Seeking During Abstinence"],"prefix":"10.64898","author":[{"given":"Kanako","family":"Matsumura","sequence":"first","affiliation":[{"name":"Interdisciplinary Neuroscience Program, The University of Texas at Austin, Austin, TX, USA, 78712"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Polina","family":"Lyuboslavsky","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, The University 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78712"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Garza","sequence":"additional","affiliation":[{"name":"Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA, 78712"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anjali","family":"Baratham","sequence":"additional","affiliation":[{"name":"Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA, 78712"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7489-9977","authenticated-orcid":false,"given":"Lauren K.","family":"Dobbs","sequence":"additional","affiliation":[{"name":"Interdisciplinary Neuroscience Program, The University of Texas at Austin, Austin, TX, USA, 78712"},{"name":"Department of Neuroscience, The University of Texas at Austin, Austin, TX, USA, 78712"},{"name":"Waggoner Center for Alcohol and Addiction Research, The University of Texas at 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