Psychedelic-Induced Serotonin 2A Receptor Downregulation Does Not Predict Swim Stress Coping in Mice

Serotoninergic psychedelics like psilocybin can produce lasting reductions in depressive symptoms, but their mechanism is unclear. In a mouse forced swim test model, the psychedelic DOI was tested for effects on behavior and 5-HT2A receptor levels in the medial prefrontal cortex. Mice exposed to swim stress developed passive coping behavior six days later, but this was not linked to increased head twitch responses or consistent changes in 5-HT2A receptor levels. A low dose of DOI (0.2 mg/kg) unexpectedly increased immobility, while a high dose (2 mg/kg) had no significant effect. DOI did cause a dose-dependent decrease in 5-HT2A levels in stressed mice. These results do not support the idea that downregulating 5-HT2A receptors in the medial prefrontal cortex underlies antidepressant-like effects of serotoninergic psychedelics.

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Abstract

Serotoninergic psychedelics such as psilocybin have been reported to elicit a long-lasting reduction in depressive symptoms. Although the main target for serotoninergic psychedelics, serotonin type 2A receptor (5-HT2A), has been established, the possible mechanism of the antidepressant action of psychedelics remains unknown. Using the mouse forced swim test model, we examined whether the administration of the synthetic serotoninergic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) would modulate 5-HT2A receptor levels in the medial prefrontal cortex (mPFC) and revert stress-induced changes in behavior. Mice subjected to swim stress developed a passive stress-coping strategy when tested in the forced swim test 6 days later. This change in behavior was not associated with the hypothesized increase in 5-HT2A receptor-dependent head twitch behaviors or consistent changes in 5-HT2A receptor levels in the mPFC. When DOI was administered 1 day before the forced swim test, a low dose (0.2 mg/kg i.p.) unexpectedly increased immobility while a high dose (2 mg/kg i.p.) had no significant effect on immobility. Nevertheless, DOI evoked a dose-dependent decrease in 5-HT2A levels in the mPFC of mice previously exposed to swim stress. Our findings do not support the hypothesis that the downregulation of 5-HT2A receptors in the mPFC contributes to the antidepressant-like properties of serotoninergic psychedelics.