{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:22:19Z","timestamp":1768512139748,"version":"3.49.0"},"posted":{"date-parts":[[2024,6,1]]},"group-title":"Neuroscience","reference-count":93,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Preclinical and human studies indicate psilocybin may reduce perseverant maladaptive behaviors, including nicotine and alcohol seeking. Such studies in the opioid field are lacking, though opioids are involved in more &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 mg\/kg\/infusion of heroin, or relapse following forced abstinence. Psilocybin did not alter heroin taking, but a single exposure to 3.0 mg\/kg psilocybin 4-24 hours 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 hours later for RNA-sequencing. 3.0 mg\/kg psilocybin regulated \u223c2-fold more genes in the PFC than 1.0 mg\/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":"10.1101\/2024.05.28.596205","type":"posted-content","created":{"date-parts":[[2024,6,1]],"date-time":"2024-06-01T21:40:13Z","timestamp":1717278013000},"source":"Crossref","is-referenced-by-count":1,"title":["Psilocybin reduces heroin seeking behavior and modulates inflammatory gene expression in the nucleus accumbens and prefrontal cortex of male rats"],"prefix":"10.64898","author":[{"given":"Gabriele","family":"Floris","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konrad R.","family":"Dabrowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary 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