Psychopharmacology · 2026
Investigation of the pharmacological and circuit basis for psychedelic drug effects on interval timing in mice.
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Klein Landon M, Kopelman Jared, Sharp Richard F, Powell Susan B, Geyer Mark A, Young Jared W, Halberstadt Adam L
Аннотация
RATIONALE: Classical psychedelic drugs such as the tryptamine psilocybin can alter temporal perception. Previously, the phenylethylamine psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI), a 5-HT2A receptor agonist, altered timing precision and accuracy in mice performing the discrete-trials temporal discrimination task (TDT), a retrospective timing task where subjects differentially respond depending on whether a light is illuminated for shorter or longer than 6.5 s.
OBJECTIVES: Although DOI alters TDT performance, it is unclear whether timing is altered by tryptamine psychedelics, which are less selective for 5-HT2 subtypes and also activate the 5-HT1A receptor.
METHODS: To address this knowledge gap, we tested psilocin (the active metabolite of psilocybin) in male C57BL/6J mice performing the TDT and assessed the involvement of 5-HT1A and 5-HT2A receptors in its effects. Because the prefrontal cortex (PFC) is involved in psychedelic drug effects and temporal perception, additional experiments tested whether DOI microinfusion into the medial PFC (mPFC) replicates its systemic effects.
RESULTS: Psilocin (0.8 mg/kg SC) altered timing accuracy and precision in mice performing the TDT, similarly to DOI. Psilocin effects were blocked by the 5-HT2A antagonist M100907 but were unaffected by the 5-HT1A antagonist WAY-100,635. Infusion of DOI bilaterally into mPFC mimicked the effect of systemic administration on TDT performance. Administration of the selective 5-HT2A inverse agonists M100907 and MDL 11,939 altered timing accuracy, demonstrating that both increases and reductions in 5-HT2A receptor activation can modulate perceived clock speed.
CONCLUSIONS: The mPFC appears to play a role in TDT performance and may mediate the effects of psychedelic drugs on interval timing.
OBJECTIVES: Although DOI alters TDT performance, it is unclear whether timing is altered by tryptamine psychedelics, which are less selective for 5-HT2 subtypes and also activate the 5-HT1A receptor.
METHODS: To address this knowledge gap, we tested psilocin (the active metabolite of psilocybin) in male C57BL/6J mice performing the TDT and assessed the involvement of 5-HT1A and 5-HT2A receptors in its effects. Because the prefrontal cortex (PFC) is involved in psychedelic drug effects and temporal perception, additional experiments tested whether DOI microinfusion into the medial PFC (mPFC) replicates its systemic effects.
RESULTS: Psilocin (0.8 mg/kg SC) altered timing accuracy and precision in mice performing the TDT, similarly to DOI. Psilocin effects were blocked by the 5-HT2A antagonist M100907 but were unaffected by the 5-HT1A antagonist WAY-100,635. Infusion of DOI bilaterally into mPFC mimicked the effect of systemic administration on TDT performance. Administration of the selective 5-HT2A inverse agonists M100907 and MDL 11,939 altered timing accuracy, demonstrating that both increases and reductions in 5-HT2A receptor activation can modulate perceived clock speed.
CONCLUSIONS: The mPFC appears to play a role in TDT performance and may mediate the effects of psychedelic drugs on interval timing.