Floris Gabriele, Dabrowski Konrad R, Zanda Mary Tresa, Daws Stephanie E
Center for Substance Abuse Research, Temple University, Philadelphia, PA, USA.
Department of Neural Sciences, Temple University, Philadelphia, PA, USA.
Mol Psychiatry. 2025 May;30(5):1801-1816. doi: 10.1038/s41380-024-02788-y. Epub 2024 Oct 21.
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-HTR), a well-documented target for modulation of drug seeking, and evidence suggests 5-HTR 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-HTR 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-HTR 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.
临床前研究和人体研究表明，裸盖菇素可能会减少顽固的适应不良行为，包括对尼古丁和酒精的觅求行为。尽管阿片类药物与超过50%的过量用药死亡有关，但在阿片类药物领域缺乏此类研究。裸盖菇素是5-羟色胺2A受体（5-HTR）的激动剂，这是一个已被充分证明的调节觅药行为的靶点，并且有证据表明5-HTR激动剂可能会减弱对阿片类药物的动机。我们试图在海洛因自我给药（SA）大鼠模型中研究裸盖菇素在介导阿片类药物使用戒断和维持长期戒除阿片类药物觅求行为方面的治疗效果。在给予0.075mg/kg/次海洛因进行自我给药或强制戒断后复发之前，将裸盖菇素或5-HTR拮抗剂酮色林和沃利色林全身给药于大鼠。裸盖菇素并未改变海洛因的摄取量，但在复发测试前4 - 24小时单次给予3.0mg/kg裸盖菇素可减弱线索诱导的海洛因觅求行为。相反，5-HTR拮抗剂加剧了海洛因复发。为了开始阐明裸盖菇素的作用机制，对未接触过药物的大鼠给予裸盖菇素和/或酮色林，并在24小时后从内侧前额叶皮质（PFC）收集组织，内侧前额叶皮质是对觅药行为至关重要且对裸盖菇素敏感的区域，用于RNA测序。3.0mg/kg裸盖菇素在内侧前额叶皮质中调节的基因数量比1.0mg/kg时多约2倍，包括参与细胞骨架和细胞因子信号传导的基因。酮色林阻断了超过90%的裸盖菇素调节的基因，包括IL-17a细胞因子受体Il17ra。已有报道称致幻化合物具有抗炎特性，因此我们进行了基因表达阵列分析，以测量在表现出裸盖菇素介导的海洛因觅求抑制作用的动物的内侧前额叶皮质中的趋化因子/细胞因子分子。裸盖菇素调节了4个基因，包括Il-17a，以及与复发行为相关的一组基因。内侧前额叶皮质IL-17a的选择性抑制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，其也可减少海洛因觅求行为。
