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Incubated cocaine-craving is associated with increased extracellular glutamate within the medial prefrontal cortex (mPFC) and this release, particularly within the prelimbic (PL) subregion, is necessary for incubated cocaine-craving. A potential candidate mediating these incubation-driving effects of glutamate release within the PL are alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To investigate the role of mPFC AMPA receptors (AMPARs) in incubated craving, male and female Sprague-Dawley rats were trained to self-administer cocaine for 6 h\/day for 10 consecutive days. Either during early or later withdrawal, rats were infused intra-PL with the AMPA\/kainate receptor antagonist NBQX (0 or 1 \u00b5g\/0.5 \u00b5l per side), followed by 30-min tests for cue-induced responding. Immunoblotting was also conducted to relate the expression of incubated cocaine- and sucrose-craving to AMPAR subunit expression within mPFC subregions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Intra-PL NBQX blocked incubated craving expressed in late, but not early, withdrawal. In contrast, an intra-PL NBQX infusion increased cue-induced cocaine-seeking in female rats tested in early withdrawal. No incubation-related changes in AMPAR subunit expression were detected within the PL or IL of rats of either sex and no estrus-associated changes in subunit expression were detected in female rats exhibiting incubated cocaine-craving. In contrast, elevated GluA1 expression was observed within the IL of male rats exhibiting an incubation of sucrose-craving.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Together, these findings indicate a necessary role for AMPAR\/kainate receptors within the PL in driving incubated cocaine-craving and suggest that AMPAR\/kainate receptors located within the IL may be involved also in sucrose-craving selectively in males.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fpsyt.2025.1627477","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T05:34:43Z","timestamp":1755149683000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["AMPA\/kainate receptor activation within the prelimbic cortex is necessary for incubated cocaine-craving"],"prefix":"10.3389","volume":"16","author":[{"given":"Laura L.","family":"Huerta Sanchez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirette G.","family":"Tadros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoa H. 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