5-HT2A receptor activation is dispensable for psilocybin-induced fear extinction and neuroplasticity in mice.

Abstract

Psilocybin facilitates fear extinction in rodents, but its clinical utility is hampered by 5-hydroxytryptamine (5-HT) 2A-receptor-mediated hallucinogenic effects. This study aimed to explore whether 5-HT2A receptor is obligatory for psilocybin's fear extinction and neuroplasticity effect. Male C57BL/6J mice underwent auditory-cue fear conditioning. Ketanserin (5-HT2A/2C antagonist) or MDL100907 (selective 5-HT2A antagonist) was administered 30 min before a single psilocybin (2.5 mg/kg, intraperitoneal) or vehicle injection. Mice were fear-conditioned 2 days before psilocybin administration, extinction training commenced 30 min after the psilocybin injection, and extinction testing was performed 24 h later. The mice were euthanized 1.5 h after behavioral testing in the MDL100907 antagonism experiment, and hippocampal and medial prefrontal cortex (mPFC) tissues were collected. Western blotting and enzyme-linked immunosorbent assay (ELISA) were used to detect brain-derived neurotrophic factor (BDNF) protein expression. Immunofluorescence staining was used to assess the number of doublecortin-positive cells in the hippocampal dentate gyrus (DG). In extinction testing, mice that received psilocybin combined with either ketanserin or MDL100907 still exhibited a significantly lower freezing response than those treated with antagonist alone. MDL100907 pretreatment failed to block the psilocybin-evoked upregulation of BDNF in both hippocampus and mPFC. Likewise, the increase in doublecortin (DCX)-positive newborn neurons in the DG induced by psilocybin remained intact after MDL100907 blockade. The effects of psilocybin in facilitating fear extinction and increasing neuroplasticity in fear-conditioned mice are not dependent on 5-HT2A receptor activation, which supports that its therapeutic and hallucinogenic effects can be dissociated.

In the evidence

This study is part of the evidence base for 2 syntheses in the library. Here is how each one recorded it.

• State of the evidence: Neuroplasticity ↑Supports

  Psilocybin facilitated fear extinction and increased BDNF and doublecortin-positive neurons even when the 5-HT2A receptor was blocked, indicating these effects are not dependent on 5-HT2A receptor activation.

  Synthesized September 20, 2026

• State of the evidence: Psilocybin ↑Supports

  Psilocybin facilitated fear extinction and increased BDNF and doublecortin-positive neurons even when the 5-HT2A receptor was blocked, indicating these effects are not dependent on 5-HT2A activation.

  Synthesized September 20, 2026

Comparable studies

Other preclinical and animal studies on neuroplasticity, most cited first.