MDMA and psilocybin regulate oligodendrocyte-lineage cell numbers and anxiety-like behaviors in a rat model of fear.

Psilocybin and MDMA reduce anxiety-like behaviors in a rat model of fear conditioning, and these effects depend on myelin plasticity in the dentate gyrus. Both drugs triggered oligodendroglial changes and multi-omic signatures of myelin remodeling, though mean myelin thickness (g-ratio) did not differ significantly between treated and untreated fear-conditioned animals. Disrupting myelin abolished the anxiolytic effects. Psilocybin preferentially activated early oligodendroglial gene programs, while MDMA enhanced markers of mature myelin. Blocking the 5-HT2A receptor completely eliminated both the myelin and behavioral enhancements. Enhancing myelination may be a viable strategy to sustain therapeutic effects of psychedelic-assisted treatments for PTSD.

Study at a glance

Abstract

Psilocybin and 3,4-methylenedioxymethamphetamine (MDMA) produce rapid, enduring therapeutic effects in post-traumatic stress disorder (PTSD); however, the underlying cellular mechanisms remain incompletely understood. This study investigated whether adult myelin plasticity contributes to the therapeutic actions of psilocybin and MDMA in a rat model of contextual fear conditioning. Adult male Wistar rats (n = 210) received repeated low doses of psilocybin (0.5 mg/kg, i.p., for four days) or MDMA (0.1 mg/kg/day, i.p., for four days). Behavioral tests assessed anxiety-like behaviors and spatial memory. Following local and global manipulations of myelin integrity, we assessed the drugs' effects on myelination by quantifying myelin sheath thickness, oligodendrocyte-lineage cell densities, and transcriptomic, proteomic, and metabolomic profiles in the dentate gyrus. Both compounds reduced anxiety-like behaviors. These improvements coincided with oligodendroglial changes and multi-omic signatures of myelin-related remodeling; mean g-ratio measures of myelin thickness, however, did not differ significantly between intact fear-conditioned animals with or without psychedelic treatment. Myelin disruption abolished these anxiolytic effects, and integrative multi-omics revealed convergent upregulation of myelin-related proteins following administration of psilocybin or MDMA. Psilocybin preferentially induced early oligodendroglial gene programs, while MDMA enhanced markers of mature myelin. Notably, 5-HT2A receptor blockade completely abolished the myelin and behavioral enhancements induced by both psilocybin and MDMA. Psilocybin and MDMA promote adult oligodendrocyte and myelin plasticity. Enhancing myelination might be a viable strategy to augment or sustain the therapeutic effects of psychedelic-assisted treatments for PTSD and related disorders.