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This has been modeled in rodents using the incubation of craving model, in which cue-induced drug seeking increases over the first weeks of abstinence from drug self-administration and then remains high for an extended period. Incubation has been reported for several opioids, including oxycodone, but little is known about underlying synaptic plasticity. In contrast, it is well established that incubation of cocaine and methamphetamine craving depends on strengthening of glutamate synapses in the nucleus accumbens (NAc) through incorporation of calcium-permeable AMPARs (CP-AMPARs). CP-AMPARs have higher conductance than the calcium-impermeable AMPARs that mediate NAc excitatory transmission in drug-na\u00efve animals, as well as other distinct properties. Here we examined AMPAR transmission in medium spiny neurons (MSN) of NAc core and shell subregions in rats during forced abstinence from extended-access oxycodone self-administration. In early abstinence (prior to incubation), CP-AMPAR levels were low. After 17-33 days of abstinence (when incubation is stably plateaued), CP-AMPAR levels were significantly elevated in both subregions. These results explain the prior demonstration that infusion of a selective CP-AMPAR antagonist into NAc core or shell subregions prevents expression of oxycodone incubation. Then, using transgenic rats, we found CP-AMPAR upregulation on both D1 and D2 receptor-expressing MSN, which contrasts with selective upregulation on D1 MSN after cocaine and methamphetamine incubation. Overall, our results demonstrate a common role for CP-AMPAR upregulation in psychostimulant and oxycodone incubation, albeit with differences in MSN subtype-specificity.<\/jats:p>","DOI":"10.1101\/2025.04.06.647399","type":"posted-content","created":{"date-parts":[[2025,4,6]],"date-time":"2025-04-06T22:10:16Z","timestamp":1743977416000},"source":"Crossref","is-referenced-by-count":0,"title":["Incubation of oxycodone craving is associated with CP-AMPAR upregulation in D1 and D2 receptor-expressing medium spiny neurons in nucleus accumbens core and shell"],"prefix":"10.64898","author":[{"given":"Kimberley A.","family":"Mount","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1315-4685","authenticated-orcid":false,"given":"Hayley M.","family":"Kuhn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8199-9133","authenticated-orcid":false,"given":"Eun-Kyung","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madelyn M.","family":"Beutler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9129-3432","authenticated-orcid":false,"given":"Marina E.","family":"Wolf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025040903101152000_2025.04.06.647399v1.1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1369-1600.2010.00281.x"},{"key":"2025040903101152000_2025.04.06.647399v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.08.019"},{"key":"2025040903101152000_2025.04.06.647399v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(03)03165-2"},{"key":"2025040903101152000_2025.04.06.647399v1.4","doi-asserted-by":"publisher","DOI":"10.3389\/fnsyn.2021.799274"},{"key":"2025040903101152000_2025.04.06.647399v1.5","doi-asserted-by":"crossref","unstructured":"Alonso-Caraballo Y , Li Y , Constantino NJ , Neal MA , Driscoll GS , Mavrikaki M , Bolshakov VY , Chartoff EH (2024) Sex-specific behavioral and thalamo-accumbal circuit adaptations after oxycodone abstinence. bioRxiv.","DOI":"10.1101\/2024.08.01.605459"},{"key":"2025040903101152000_2025.04.06.647399v1.6","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2021.697509"},{"key":"2025040903101152000_2025.04.06.647399v1.7","doi-asserted-by":"publisher","DOI":"10.1111\/adb.12927"},{"key":"2025040903101152000_2025.04.06.647399v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2018.10.009"},{"key":"2025040903101152000_2025.04.06.647399v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-018-0125-6"},{"key":"2025040903101152000_2025.04.06.647399v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2010.07.014"},{"key":"2025040903101152000_2025.04.06.647399v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.02.018"},{"key":"2025040903101152000_2025.04.06.647399v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2019.07.030"},{"key":"2025040903101152000_2025.04.06.647399v1.13","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-018-1318-z"},{"key":"2025040903101152000_2025.04.06.647399v1.14","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.13955"},{"key":"2025040903101152000_2025.04.06.647399v1.15","doi-asserted-by":"crossref","unstructured":"Bossert JM , Townsend EA , Altidor L , Fredriksson I , Shekara A , Husbands S , Sulima A , Rice KC , Banks ML , Shaham Y (2021) Sex differences in the effect of chronic delivery of the buprenorphine analog BU08028 on heroin relapse and choice in a rat model of opioid maintenance. 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