{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:36:08Z","timestamp":1785411368546,"version":"3.56.0"},"posted":{"date-parts":[[2025,6,25]]},"group-title":"Neuroscience","reference-count":75,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T00:00:00Z","timestamp":1750809600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01DA011289"],"award-info":[{"award-number":["R01DA011289"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01DA055645"],"award-info":[{"award-number":["R01DA055645"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Washington State University Alcohol and Drug Abuse Research Program"},{"name":"Stanford University's Dean Award"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,25]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Stress is a potent trigger for drug-seeking behaviors in both rodents and humans with a history of substance use. Kappa opioid receptors (kORs) play a critical role in mediating stress responses. Our previous studies in the ventral tegmental area (VTA) demonstrated that acute stress activates kORs to block long-term potentiation at GABA\n                  <jats:sub>A<\/jats:sub>\n                  synapses on dopamine neurons (LTP\n                  <jats:sub>GABA<\/jats:sub>\n                  ) and triggers stress-induced reinstatement of cocaine seeking. Here we identify the specific GABAergic afferents affected by stress, the precise localization of kORs within the VTA, and show that VTA kOR activation is sufficient to drive reinstatement.\n                <\/jats:p>\n                <jats:p>\n                  We optogenetically activated specific GABAergic afferents and found that nucleus accumbens (NAc)-to-VTA, but not lateral hypothalamus (LH)-to-VTA projections, exhibit stress-sensitive LTP\n                  <jats:sub>GABA<\/jats:sub>\n                  . Using a conditional knock-out approach, we found that selectively deleting kORs from NAc neurons but not from dopamine cells prevents stress-induced block of LTP\n                  <jats:sub>GABA<\/jats:sub>\n                  . Selectively activating dynorphin-containing NAc neurons with an excitatory DREADD mimics acute stress, preventing LTP\n                  <jats:sub>GABA<\/jats:sub>\n                  at VTA synapses. We furthermore demonstrated that without acute stress, microinjection of a selective kOR agonist directly into the VTA facilitates cocaine reinstatement without similarly affecting sucrose-motivated responding, demonstrating the critical role of kORs in stress-induced cocaine reinstatement.\n                <\/jats:p>\n                <jats:p>\n                  Our results show that kORs on GABAergic NAc nerve terminals in the VTA underlie loss of LTP\n                  <jats:sub>GABA<\/jats:sub>\n                  that may drive stress-induced addiction-related behaviors. Our work highlights the importance of inhibitory inputs for controlling dopamine neuron excitability in the context of addiction and contributes to defining the circuit involved in stress-induced drug reinstatement.\n                <\/jats:p>","DOI":"10.1101\/2025.06.23.661181","type":"posted-content","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T15:15:14Z","timestamp":1750864514000},"source":"Crossref","is-referenced-by-count":1,"title":["Kappa opioid receptors control a stress-sensitive brain circuit and drive cocaine seeking"],"prefix":"10.64898","author":[{"given":"Valentina Martinez","family":"Damonte","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Nancy Pritzker Laboratory, Stanford University, Stanford, CA 94305, US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia G.","family":"Bailey","sequence":"additional","affiliation":[{"name":"Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA 99163, US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Thakar","sequence":"additional","affiliation":[{"name":"Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA 99163, US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Stralka","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Nancy Pritzker Laboratory, Stanford University, Stanford, CA 94305, US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Travis E.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA 99163, US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Kauer","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Nancy 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