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Recently, our laboratory identified heightened mTOR activity in the prelimbic (PL) and infralimbic (IL) subregions of the medial prefrontal cortex (mPFC) as being associated with incubated craving for cocaine and sucrose, respectively. Importantly, Everolimus, an FDA\u2010approved mTOR inhibitor, blocked the expression of incubated craving for both reinforcers. Hence, our current study investigated whether mTOR signalling also underpins cue\u2010induced methamphetamine (METH)\u2010seeking by evaluating the \u201ctherapeutic potential\u201d of Everolimus to block incubated METH\u2010craving. Male and female rats were trained under extended\u2010access procedures (6\u2010h\/day\u2009\u00d7\u200910\u2009days) to self\u2010administer intravenous METH (0.1\u2009mg\/kg\/0.1\u2009mL infusion), paired with the presentation of a 20\u2010s light + tone compound stimulus and then were subjected to a withdrawal period of 1 or 30\u2009days (WD1 or WD30). Rats tested on WD30 were gavage\u2010infused with either vehicle (VEH; 1% DMSO in water; vol: 1\u2009mL\/kg) or Everolimus (1 or 10\u2009mg\/kg), whereas WD1 rats were infused with VEH to index baseline craving. Thirty minutes later, rats underwent a 2\u2010h test to measure cue\u2010elicited responding. Akt\/mTOR activity in the PL and IL was examined via immunoblotting procedures. Male and female rats exhibited comparable METH intake and craving, with no effect of estrous cycle observed for either measure in females. Unlike previous findings for incubated cocaine\u2010 and sucrose\u2010craving, Everolimus did not reduce incubated METH\u2010craving. Further, incubated METH\u2010craving was not associated with changes in Akt\/mTOR activation within mPFC subregions nor did Everolimus lower mTOR pathway activation below baseline levels in either METH\u2010experienced or \u2013naive rats. Together, these findings demonstrate that elevated mTOR signalling within mPFC is not involved in incubated METH\u2010craving, highlighting the potential need for drug\u2010specific targeted treatments for curbing incubated craving in protracted withdrawal.<\/jats:p>","DOI":"10.1111\/adb.70189","type":"journal-article","created":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T23:41:08Z","timestamp":1789342868000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Systemic Everolimus Does Not Block the Incubation of Methamphetamine\u2010Craving: A Dose\u2013Response Study"],"prefix":"10.1111","volume":"31","author":[{"given":"Fernando J.","family":"Cano","sequence":"first","affiliation":[{"name":"Department of Psychological and Brain Sciences University of California Santa Barbara  Santa Barbara California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0585-9460","authenticated-orcid":false,"given":"Kierra E.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Psychological and Brain Sciences University of California Santa Barbara  Santa Barbara California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Stuemke","sequence":"additional","affiliation":[{"name":"Department of Psychological and Brain Sciences University of California Santa Barbara  Santa Barbara California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9885-7473","authenticated-orcid":false,"given":"Asha","family":"Jotwani","sequence":"additional","affiliation":[{"name":"Department of Psychological and Brain Sciences University of California Santa Barbara  Santa Barbara California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Lassers","sequence":"additional","affiliation":[{"name":"Department of Psychological and Brain Sciences University of California Santa Barbara  Santa Barbara California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly M.","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Psychological and Brain Sciences University of California Santa Barbara  Santa Barbara California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonya D.","family":"Adler","sequence":"additional","affiliation":[{"name":"Department of Psychological and Brain Sciences University of California Santa Barbara  Santa Barbara California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0870-8252","authenticated-orcid":false,"given":"Laura L.","family":"Huerta Sanchez","sequence":"additional","affiliation":[{"name":"Department of Psychological and Brain Sciences University of California Santa Barbara  Santa Barbara California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J. 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