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Relapse is a major challenge in the treatment of CUD, and people living with HIV (PLWH) exhibit shorter time to relapse. One driver of relapse may be re-exposure to cocaine, which can be modeled in rodents using cocaine-primed reinstatement. This process involves neuroadaptations within the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) shell, regions that mediate cocaine reward learning and relapse-related behavior. HIV infection interacts with cocaine to alter corticostriatal circuits, which may further dysregulate cocaine seeking. To investigate the impact of HIV infection on cocaine reward learning and reinstatement and the role of mPFC-NAc circuits, we utilized the EcoHIV mouse model, a chimeric form of HIV-1 which can infect wild-type mice. Our findings demonstrate that EcoHIV infection enhances cocaine-primed reinstatement. We also observed increased cocaine-induced expression of the cellular activation marker cFos in the NAshell in EcoHIV-infected mice. Given the role of the mPFC-NAshell circuit in cocaine-seeking behaviors, we further demonstrated that chemogenetic activation of this circuit could reverse the behavioral deficits induced by EcoHIV. We propose that HIV infection contributes to neuroadaptations in the mPFC-NAshell circuit, and enhancing its activity may inhibit relapse-related behavior. These findings indicate that key neuronal circuits underlying cocaine reinstatement are similarly implicated in HIV infection and suggest potential strategies for managing relapse in PLWH.<\/jats:p>","DOI":"10.1007\/s00213-025-06849-0","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T06:58:28Z","timestamp":1752649108000},"page":"1309-1322","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chemogenetic activation of medial prefrontal cortex projections to the nucleus accumbens shell suppresses cocaine-primed reinstatement in EcoHIV infected mice"],"prefix":"10.1007","volume":"243","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8888-491X","authenticated-orcid":false,"given":"Qiaowei","family":"Xie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark D.","family":"Namba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohan","family":"Dasari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren A.","family":"Buck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine M.","family":"Side","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel L.","family":"Goldberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyewon","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua G.","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Giacometti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1176-5397","authenticated-orcid":false,"given":"Jacqueline M.","family":"Barker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,16]]},"reference":[{"key":"6849_CR1","doi-asserted-by":"crossref","unstructured":"Anderson SM, Famous KR, Sadri-Vakili G, Kumaresan V, Schmidt HD, Bass CE, Terwilliger EF, Cha JHJ, Pierce RC (2008) CaMKII: a biochemical bridge linking accumbens dopamine and glutamate systems in cocaine seeking. 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