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Such studies in the opioid field are lacking, though opioids are involved in &gt;50% of overdose deaths. Psilocybin is an agonist at the serotonin 2A receptor (5-HT\n                    <jats:sub>2A<\/jats:sub>\n                    R), a well-documented target for modulation of drug seeking, and evidence suggests 5-HT\n                    <jats:sub>2A<\/jats:sub>\n                    R agonists may dampen motivation for opioids. We sought to investigate the therapeutic efficacy of psilocybin in mediating cessation of opioid use and maintenance of long-lasting abstinence from opioid seeking behavior in a rat model of heroin self-administration (SA). Psilocybin or 5-HT\n                    <jats:sub>2A<\/jats:sub>\n                    R antagonists ketanserin and volinanserin were administered systemically to rats prior to SA of 0.075\u2009mg\/kg\/infusion of heroin, or relapse following forced abstinence. Psilocybin did not alter heroin taking, but a single exposure to 3.0\u2009mg\/kg psilocybin 4\u201324\u2009h prior to a relapse test blunted cue-induced heroin seeking. Conversely, 5-HT\n                    <jats:sub>2A<\/jats:sub>\n                    R antagonists exacerbated heroin relapse. To begin to elucidate mechanisms of psilocybin, drug-na\u00efve rats received psilocybin and\/or ketanserin, and tissue was collected from the prefrontal cortex (PFC), a region critical for drug seeking and responsive to psilocybin, 24\u2009h later for RNA-sequencing. 3.0\u2009mg\/kg psilocybin regulated ~2-fold more genes in the PFC than 1.0\u2009mg\/kg, including genes involved in the cytoskeleton and cytokine signaling. Ketanserin blocked &gt;90% of psilocybin-regulated genes, including the IL-17a cytokine receptor,\n                    <jats:italic>Il17ra<\/jats:italic>\n                    . Psychedelic compounds have reported anti-inflammatory properties, and therefore we performed a gene expression array to measure chemokine\/cytokine molecules in the PFC of animals that displayed psilocybin-mediated inhibition of heroin seeking. Psilocybin regulated 4 genes, including\n                    <jats:italic>Il17a<\/jats:italic>\n                    , and a subset of genes correlated with relapse behavior. Selective inhibition of PFC IL-17a was sufficient to reduce heroin relapse. We conclude that psilocybin reduces heroin relapse and highlight IL-17a signaling as a potential downstream pathway of psilocybin that also reduces heroin seeking.\n                  <\/jats:p>","DOI":"10.1038\/s41380-024-02788-y","type":"journal-article","created":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T09:03:01Z","timestamp":1729501381000},"page":"1801-1816","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Psilocybin reduces heroin seeking behavior and modulates inflammatory gene expression in the nucleus accumbens and prefrontal cortex of male rats"],"prefix":"10.1038","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5818-774X","authenticated-orcid":false,"given":"Gabriele","family":"Floris","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0545-4576","authenticated-orcid":false,"given":"Konrad R.","family":"Dabrowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Tresa","family":"Zanda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4913-8997","authenticated-orcid":false,"given":"Stephanie E.","family":"Daws","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,21]]},"reference":[{"key":"2788_CR1","first-page":"1","volume":"406","author":"H Hedegaard","year":"2021","unstructured":"Hedegaard H, Mini\u00f1o AM, Warner M. 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