{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:01:47Z","timestamp":1785420107523,"version":"3.56.0"},"posted":{"date-parts":[[2025,1,25]]},"group-title":"Neuroscience","reference-count":55,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,1,25]],"date-time":"2025-01-25T00:00:00Z","timestamp":1737763200000},"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":["R01DA052953"],"award-info":[{"award-number":["R01DA052953"]}],"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":["5R01DA037216"],"award-info":[{"award-number":["5R01DA037216"]}],"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":["DA049139"],"award-info":[{"award-number":["DA049139"]}],"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":["DA048055"],"award-info":[{"award-number":["DA048055"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100004945","name":"Michigan Department of Military and Veterans Affairs","doi-asserted-by":"crossref","award":["IO1BX004440"],"award-info":[{"award-number":["IO1BX004440"]}],"id":[{"id":"10.13039\/100004945","id-type":"DOI","asserted-by":"crossref"}]},{"award":["Roy J. Carver Charitable Trust"],"award-info":[{"award-number":["Roy J. Carver Charitable Trust"]}],"id":[{"id":"https:\/\/ror.org\/036jqmy94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,4,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The ongoing opioid crisis underscores the need for innovative treatments targeting the neurobiological mechanisms underlying opioid-seeking behaviors and relapse. Here, we explored the role of carbonic anhydrase 4 (CA4) in modulating synaptic adaptations to oxycodone withdrawal in mice. We disrupted CA4 genetically and inhibited it pharmacologically with acetazolamide (AZD), a carbonic anhydrase inhibitor used clinically. We found that oxycodone withdrawal increased AMPAR\/NMDAR ratio and synaptic recruitment of calcium-permeable AMPARs in nucleus accumbens core (NAcC) medium spiny neurons (MSNs). Synaptic changes required an extended period of abstinence, generalized to other opioids, including morphine and heroin, were more pronounced in D1 dopamine receptor-expressing MSNs, and were prevented by CA4 disruption. AZD administration\n                  <jats:italic>in vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  reversed the synaptic alterations, and the effects of AZD depended on CA4 and acid-sensing ion channel-1A. Interestingly, abstinence from oxycodone did not affect dendritic spine density in NAcC MSNs, in contrast to previously observed effects of abstinence from cocaine. Finally, in an oxycodone self-administration paradigm, CA4 disruption and AZD reduced drug-seeking behaviors following 30 days of forced abstinence. Together, these findings identify a critical role for CA4 in synaptic adaptations in opioid withdrawn mice and drug-seeking behavior. Moreover, they suggest pharmacological inhibitors of CA4 may hold therapeutic potential for reducing opioid-seeking and relapse in opioid use disorder.\n                <\/jats:p>","DOI":"10.1101\/2025.01.23.634619","type":"posted-content","created":{"date-parts":[[2025,1,25]],"date-time":"2025-01-25T20:40:30Z","timestamp":1737837630000},"source":"Crossref","is-referenced-by-count":1,"title":["Carbonic anhydrase 4 disruption and pharmacological inhibition reduce synaptic and behavioral adaptations following oxycodone withdrawal"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4660-4649","authenticated-orcid":false,"given":"Subhash C.","family":"Gupta","sequence":"first","affiliation":[{"name":"Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA"},{"name":"Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6710-984X","authenticated-orcid":false,"given":"Rebecca J.","family":"Taugher-Hebl","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA"},{"name":"Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Ghobbeh","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA"},{"name":"Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marshal T.","family":"Jahnke","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA"},{"name":"Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA"},{"name":"Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA"},{"name":"Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan T.","family":"LaLumiere","sequence":"additional","affiliation":[{"name":"Department of Psychological and Brain Sciences, University of Iowa, Iowa City, Iowa, USA"},{"name":"Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa, USA"},{"name":"Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Wemmie","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA"},{"name":"Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA"},{"name":"Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa, USA"},{"name":"Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA"},{"name":"Medical Scientist Training Program, University of Iowa, Iowa City, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041204571627000_2025.01.23.634619v2.1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00441954"},{"key":"2026041204571627000_2025.01.23.634619v2.2","doi-asserted-by":"crossref","unstructured":"Nosyk, B. , et al., Buprenorphine\/Naloxone vs Methadone for the Treatment of Opioid Use Disorder. 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