Psilocybin reduces heroin seeking behavior and modulates inflammatory gene expression in the nucleus accumbens and prefrontal cortex of male rats

Gabriele Floris; Konrad R Dabrowski; Mary Tresa Zanda; Stephanie E Daws

doi:10.1038/s41380-024-02788-y

Psilocybin reduces heroin seeking behavior and modulates inflammatory gene expression in the nucleus accumbens and prefrontal cortex of male rats

Mol Psychiatry. 2024 Oct 21. doi: 10.1038/s41380-024-02788-y. Online ahead of print.

Authors

Gabriele Floris^{1

2}, Konrad R Dabrowski^{1

3}, Mary Tresa Zanda^{1

2}, Stephanie E Daws^{4

5}

Affiliations

¹ Center for Substance Abuse Research, Temple University, Philadelphia, PA, USA.
² Department of Neural Sciences, Temple University, Philadelphia, PA, USA.
³ Department of Biology, Temple University, Philadelphia, PA, USA.
⁴ Center for Substance Abuse Research, Temple University, Philadelphia, PA, USA. Stephanie.daws@temple.edu.
⁵ Department of Neural Sciences, Temple University, Philadelphia, PA, USA. Stephanie.daws@temple.edu.

PMID: 39433903
DOI: 10.1038/s41380-024-02788-y

Abstract

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.

Abstract

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