International Journal of Molecular Sciences
November 16, 2022
Orr Shahar, Alexander Botvinnik, Noam Esh-Zuntz et al.
60 citations
Psilocybin and the serotonin precursor 5-HTP produce a characteristic head twitch response in mice, which is linked to the human psychedelic experience. This response depends primarily on the 5-HT2A receptor, as blocking it with M100907 reduced twitching. Activating the 5-HT1A receptor with 8-OH-DPAT also suppressed the response, while blocking the 5-HT2C receptor with RS-102221 had a bimodal effect—enhancing twitching at lower doses but reducing it at higher doses. Blocking the trace amine-associated receptor 1 (TAAR1) with EPPTB reduced 5-HTP-induced twitching but not psilocybin-induced twitching. These findings highlight multiple receptor systems that could modulate psychedelic effects and may inform therapeutic applications.
Translational psychiatry
May 10, 2023
Sandeep Singh, Alexander Botvinnik, Orr Shahar et al.
54 citations
Psilocybin reduced marble burying in mice, a behavior used to model obsessive-compulsive disorder, but this effect did not depend on the serotonin 2A or serotonin 1A receptors typically associated with psychedelic effects. The 5-HT1A agonist 8-OH-DPAT also reduced marble burying, and its effect was additive with psilocybin, while the 5-HT1A partial agonist buspirone reduced marble burying without adding to psilocybin's effect. Blocking 5-HT1A receptors with WAY100635 did not attenuate psilocybin's effect. A staggered psilocybin regimen over 3.5 hours had no effect, and the effect of a single injection was not persistent. Co-administration of buspirone blocked psilocybin's head twitch response, a rodent correlate of psychedelic effects, suggesting buspirone might block psychedelic effects without impairing anti-obsessional effects.
Molecular psychiatry
July 1, 2024
Orr Shahar, Alexander Botvinnik, Amit Shwartz et al.
37 citations
Psilocybin-containing mushroom extract (PME) may have stronger and longer-lasting effects on synaptic plasticity than chemically synthesized psilocybin (PSIL) alone. In male mice, both PME and PSIL increased synaptic proteins GAP43 and synaptophysin in brain regions linked to learning and memory, but PME increased more proteins across more brain areas after 11 days. Metabolomic analysis of the frontal cortex revealed a distinct metabolic profile for PME, with a progressive decline in purines associated with oxidative stress from vehicle to PSIL to PME. These findings suggest that other compounds in the mushroom extract contribute to enhanced neuroplasticity, though further research is needed to identify them.
bioRxiv (Cold Spring Harbor Laboratory)
July 23, 2022
Orr Shahar, Alexander Botvinnik, Noam Esh-Zuntz et al.
5 citations
preprint
Psilocybin and the serotonin precursor 5-HTP both cause a characteristic head twitch response in mice, a behavior linked to the human psychedelic experience. The head twitch response depends primarily on the 5-HT2A receptor, as blocking this receptor with volanserin reduced the response. Activating the 5-HT1A receptor also reduced head twitching. In contrast, blocking the 5-HT2C receptor had a bimodal effect, enhancing the response at lower doses but reducing it at higher doses. Blocking the trace amine associated receptor 1 (TAAR1) reduced head twitching caused by 5-HTP but not by psilocybin, indicating a differential role for this receptor. These findings identify multiple receptors that could be targeted to modulate the effects of psychedelic compounds in therapeutic settings.
Research Square
July 20, 2023
Orr Shahar, Alexander Botvinnik, Amit Shwartz et al.
3 citations
Psilocybin-containing mushroom extract (PME) produces more potent and prolonged effects on synaptic plasticity in the mouse brain than chemically synthesized psilocybin alone. In male C57Bl/6j mice, both PME and psilocybin triggered similar head twitch responses, but PME increased four synaptic proteins (GAP43, PSD95, synaptophysin, SV2A) across all brain areas studied after 11 days, whereas psilocybin only increased two proteins in the hippocampus and amygdala. Metabolomic analysis of the prefrontal cortex showed a gradient of metabolic changes from vehicle to psilocybin to PME, with declines in purines linked to oxidative stress and energy production. The findings suggest that additional compounds in the mushroom extract may enhance psilocybin's effects on brain plasticity.
bioRxiv (Cold Spring Harbor Laboratory)
July 14, 2022
Sandeep Singh, Alexander Botvinnik, Orr Shahar et al.
1 citation
preprint
In mice, psilocybin reduced marble-burying, a behavior linked to obsessive-compulsive disorder, as effectively as the antidepressant escitalopram. This effect was not blocked by a 5-HT2A antagonist or a 5-HT1A antagonist, indicating neither receptor is essential for psilocybin's anti-obsessional action. The 5-HT1A partial agonist buspirone also reduced marble-burying, but combining buspirone with psilocybin did not enhance the effect. Staggered doses of psilocybin over 3.5 hours had no effect, and the effect of a single injection was not persistent. Importantly, buspirone blocked psilocybin's head-twitch response, a rodent correlate of psychedelic effects, suggesting buspirone could prevent psychedelic effects without interfering with anti-obsessional benefits.