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

Given the potential of psilocybin to treat substance use disorders, the researchers investigated whether it could reduce heroin seeking behavior and maintain abstinence in a rat model. They also sought to identify the molecular mechanisms, particularly focusing on inflammatory pathways in the brain, that might underlie these behavioral changes.

Male rats were trained to self-administer heroin and then subjected to forced abstinence. The researchers administered psilocybin or 5-HT2A receptor antagonists (ketanserin and volinanserin) to observe their effects on heroin seeking during relapse tests. To understand the underlying biology, they performed RNA-sequencing on the prefrontal cortex (PFC) of drug-naïve rats treated with psilocybin and/or ketanserin. Finally, they used a focused qPCR array and direct intra-PFC infusion of an IL-17a antibody to test whether inhibiting this specific inflammatory pathway was sufficient to mimic the therapeutic effects of psilocybin.

Psilocybin did not change the amount of heroin the rats took during initial training, but a single 3.0 mg/kg dose significantly reduced cue-induced heroin seeking after forced abstinence. Conversely, blocking 5-HT2A receptors with antagonists exacerbated relapse behavior. Transcriptomic analysis revealed that psilocybin regulates genes related to cytokine signaling in the PFC, an effect largely blocked by ketanserin. Specifically, psilocybin treatment was associated with the downregulation of IL-17a signaling. The researchers confirmed that directly inhibiting IL-17a in the PFC was sufficient to reduce heroin relapse, suggesting that this inflammatory pathway is a key downstream mediator of psilocybin's therapeutic efficacy.

This study provides a potential neurobiological mechanism for how psychedelics might treat opioid addiction. By identifying the IL-17a inflammatory pathway as a target, the research opens new avenues for developing non-hallucinogenic or targeted therapies that could help prevent relapse in individuals struggling with opioid use disorder.