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 >50% of overdose deaths. Psilocybin is an agonist at the serotonin 2A receptor (5-HT_2AR), a well-documented target for modulation of drug seeking, and evidence suggests 5-HT_2AR 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_2AR 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 h prior to a relapse test blunted cue-induced heroin seeking. Conversely, 5-HT_2AR antagonists exacerbated heroin relapse. To begin to elucidate mechanisms of psilocybin, drug-naïve 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 h later for RNA-sequencing. 3.0 mg/kg psilocybin regulated ~2-fold more genes in the PFC than 1.0 mg/kg, including genes involved in the cytoskeleton and cytokine signaling. Ketanserin blocked >90% of psilocybin-regulated genes, including the IL-17a cytokine receptor, Il17ra. 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 Il17a, 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.

临床前和人体研究表明，裸盖菇素可以减少持续的适应不良行为，包括尼古丁和酗酒。缺乏阿片类药物领域的此类研究，尽管阿片类药物与 >50% 的过量死亡有关。裸盖菇素是 5-羟色胺 2A 受体 （5-HT_2AR） 的激动剂，是有据可查的调节药物寻求的靶标，有证据表明 5-HT_2AR 激动剂可能会抑制阿片类药物的动机。我们试图研究裸盖菇素在海洛因自我给药 （SA） 大鼠模型中介导向停止使用阿片类药物和维持阿片类药物寻求行为的长期戒断的治疗效果。裸盖菇素或 5-HT_2AR 拮抗剂酮色林和剑氨酸在 SA 为 0.075 mg/kg/输注海洛因之前，或强制戒断后复发。裸盖菇素不会改变海洛因的服用，但在复发试验前 4-24 小时单次暴露于 3.0 mg/kg 裸盖菇素会减弱线索诱导的海洛因寻找。相反，5-HT_2AR 拮抗剂加剧了海洛因复发。为了开始阐明裸盖菇素的机制，未接受过药物治疗的大鼠接受裸盖菇素和/或酮色林，并从前额叶皮层 （PFC） 收集组织，PFC 是寻找药物的关键区域，对裸盖菇素有反应，24 小时后用于 RNA 测序。3.0 mg/kg 裸盖菇素在 PFC 中调节的基因是 1.0 mg/kg 的 ~2 倍，包括参与细胞骨架和细胞因子信号传导的基因。酮色林阻断了 >90% 的裸盖菇素调节基因，包括 IL-17a 细胞因子受体 Il17ra。 迷幻化合物已报道具有抗炎特性，因此我们进行了基因表达阵列以测量动物 PFC 中的趋化因子/细胞因子分子，这些动物表现出裸盖菇素介导的对海洛因寻找的抑制。裸盖菇素调节 4 个基因，包括 Il17a，以及与复发行为相关的基因子集。选择性抑制 PFC IL-17a 足以减少海洛因复发。我们得出结论，裸盖菇素可减少海洛因复发，并强调 IL-17a 信号传导是裸盖菇素的潜在下游途径，也可以减少海洛因的寻求。