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Sex-specific role for 5-HT2A receptor in psychedelic-induced extinction of opioid rewarding properties

ABSTRACT: Emerging evidence suggests that classical psychedelics may offer therapeutic potential for opioid use disorder (OUD) by alleviating key hallmarks such as altered reward processing and dependence. However, the mechanisms behind these effects remain unclear. Our data demonstrate that a single administration of the psychedelic psilocybin (PSI) reduces conditioned behavior and withdrawal induced by the opioid oxycodone (OXY) in male mice but not in females, and this effect is mediated via the 5-HT2A receptor (5-HT2AR). We show that the sex-specific attenuation of OXY preference is driven by 5-HT2AR activation in frontal cortex pyramidal neurons projecting to the nucleus accumbens (NAc). Additionally, PSI modulates epigenomic regulation following repeated OXY exposure and induces sex-specific NAc dendritic structural plasticity independently of 5-HT2AR. Notably, female frontal cortex and NAc show fewer changes at gene enhancer regions in response to PSI, repeated OXY, or combined PSI-OXY treatment compared to males, with the frontal cortex exhibiting more pronounced sex differences than the NAc at the epigenomic level. Together, these results provide novel insights into the neural and epigenetic mechanisms of psychedelic-induced plasticity in OUD, while also highlighting sex differences in PSI's modulation of reward pathways and its therapeutic potential.

ORGANISM(S): Mus musculus

PROVIDER: GSE281878 | GEO | 2025/08/13

REPOSITORIES: GEO

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Project description:This dataset includes samples in the UTHealth Brain Collection (UTHBC) from Grimm et al 2022 "MicroRNA-mRNA networks are dysregulated in opioid use disorder postmortem brain: further evidence for opioid-induced neurovascular alterations ", doi: 10.3389/fpsyt.2022.1025346. To understand mechanisms and identify potential targets for intervention in the current crisis of opioid use disorder (OUD), postmortem brains represent an under-utilized resource. To refine previously reported gene signatures of neurobiological alterations in OUD from the dorsolateral prefrontal cortex (Brodmann Area 9, BA9), we explored the role of microRNAs (miRNA) as powerful epigenetic regulators of gene function. Building on the growing appreciation that miRNAs can cross the blood-brain barrier, we carried out miRNA profiling in same-subject postmortem samples from BA9 and blood tissues. miRNA-mRNA network analysis showed that even though miRNAs identified in BA9 and blood were fairly distinct, their target genes and corresponding enriched pathways overlapped strongly. Among the dominant enriched biological processes were tissue development and morphogenesis, and MAPK signaling pathways. These findings point to robust, redundant, and systemic opioid-induced miRNA dysregulation with potential functional impact on transcriptomic changes. Further, using correlation network analysis we identified cell-type specific miRNA targets, specifically in astrocytes, neurons, and endothelial cells, associated with OUD transcriptomic dysregulation. Finally, leveraging a collection of control brain transcriptomes from the Genotype-Tissue Expression (GTEx) project, we identified correlation of OUD miRNA targets with TGF beta, hypoxia, angiogenesis, coagulation, immune system and inflammatory pathways. These findings support previous reports of neurovascular and immune system alterations as a consequence of opioid abuse and shed new light on miRNA network regulators of cellular response to opioid drugs.

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Sex-specific role for 5-HT2A receptor in psychedelic-induced extinction of opioid rewarding properties

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