Gs signaling pathway distinguishes hallucinogenic and nonhallucinogenic 5-HT2AR agonists induced head twitch response in mice

Liu, Xiaoqian; Zhu, Huili; Gao, Huan; Tian, Xiangyun; Tan, Bo; Su, Rui‐Bin

doi:10.1016/j.bbrc.2022.01.113

Cited by 20 publications

(17 citation statements)

References 21 publications

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“…57 However, a previous mouse study showed that genetic deletion of G αq only partially reduces drug-induced HTR, 62 while another mouse study pointed to a possible role for G αs in producing psychedelic-like drug effects. 63 We found that psilocin and norpsilocin were both potent agonists in the calcium mobilization assay, and our results generally agree with those of Sherwood and colleagues. 41 Although many assays can be used to study the functional potency and efficacy of psychedelics at 5-HT 2A , 60 it is unclear which signaling pathway(s) are predictive for therapeutic or other effects.…”

Section: ■ Discussionsupporting

confidence: 92%

“…5-HT 2A and other 5-HT receptors couple to many canonical and noncanonical intracellular signaling pathways, depending on biological context, which could mediate distinct pharmacological effects of psychedelics. , In cells transfected with rat 5-HT 2A , drug potencies in the 5-HT 2A calcium mobilization assay associated with G αq signaling have been shown to predict potency for phenethylamine psychedelic-induced HTR in mice . However, a previous mouse study showed that genetic deletion of G αq only partially reduces drug-induced HTR, while another mouse study pointed to a possible role for G αs in producing psychedelic-like drug effects . We found that psilocin and norpsilocin were both potent agonists in the calcium mobilization assay, and our results generally agree with those of Sherwood and colleagues .…”

Section: Discussionmentioning

confidence: 99%

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Structure–Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice

Glatfelter

Pottie

Partilla

et al. 2022

ACS Pharmacol. Transl. Sci.

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4-Phosphoryloxy-N,N-dimethyltryptamine (psilocybin) is a naturally occurring tertiary amine found in many mushroom species. Psilocybin is a prodrug for 4-hydroxy-N,N-dimethyltryptamine (psilocin), which induces psychedelic effects via agonist activity at the serotonin (5-HT) 2A receptor (5-HT2A). Several other 4-position ring-substituted tryptamines are present in psilocybin-containing mushrooms, including the secondary amine 4-phosphoryloxy-N-methyltryptamine (baeocystin) and the quaternary ammonium 4-phosphoryloxy-N,N,N-trimethyltryptamine (aeruginascin), but these compounds are not well studied. Here, we investigated the structure–activity relationships for psilocybin, baeocystin, and aeruginascin, as compared to their 4-acetoxy and 4-hydroxy analogues, using in vitro and in vivo methods. Broad receptor screening using radioligand binding assays in transfected cells revealed that secondary and tertiary tryptamines with either 4-acetoxy or 4-hydroxy substitutions display nanomolar affinity for most human 5-HT receptor subtypes tested, including the 5-HT2A and the serotonin 1A receptor (5-HT1A). The same compounds displayed affinity for 5-HT2A and 5-HT1A in mouse brain tissue in vitro and exhibited agonist efficacy in assays examining 5-HT2A-mediated calcium mobilization and β-arrestin 2 recruitment. In mouse experiments, only the tertiary amines psilocin, psilocybin, and 4-acetoxy-N,N-dimethyltryptamine (psilacetin) induced head twitch responses (ED50 0.11–0.29 mg/kg) indicative of psychedelic-like activity. Head twitches were blocked by 5-HT2A antagonist pretreatment, supporting 5-HT2A involvement. Both secondary and tertiary amines decreased body temperature and locomotor activity at higher doses, the effects of which were blocked by 5-HT1A antagonist pretreatment. Across all assays, the pharmacological effects of 4-acetoxy and 4-hydroxy compounds were similar, and these compounds were more potent than their 4-phosphoryloxy counterparts. Importantly, psilacetin appears to be a prodrug for psilocin that displays substantial serotonin receptor activities of its own.

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Section: ■ Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Structure–Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice

Glatfelter

Pottie

Partilla

et al. 2022

ACS Pharmacol. Transl. Sci.

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show abstract

“…Notably, these regions matched those with the highest density of 5HT 2a and 5HT 1a neuroreceptors. This relationship is plausible given that psilocin (psilocybin's active metabolite) is known to have an appreciable-to-high affinity for the 5-HT1A and 2A receptors, respectively, where it acts as an agonist; in the case of the 5-HT2AR, potentially stimulating plasticity-related signaling cascades relevant to an antidepressant action (Desouza et al, 2021;Liu et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Brain dynamics predictive of response to psilocybin for treatment-resistant depression

Vohryzek

Cabral

Lord

et al. 2022

Preprint

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Psilocybin therapy for depression has started to show promise, yet the underlying causal mechanisms are not currently known. Here we leveraged the differential outcome in responders and non-responders to psilocybin (10mg and 25mg, 7 days apart) therapy for depression - to gain new insights into regions and networks implicated in the restoration of healthy brain dynamics. We used whole-brain modelling to fit the spatiotemporal brain dynamics at rest in both responders and non-responders before treatment. Dynamic sensitivity analysis of systematic perturbation of these models enabled us to identify specific brain regions implicated in a transition from a depressive brain state to a heathy one. Binarizing the sample into treatment responders (>50% reduction in depressive symptoms) versus non-responders enabled us to identify a subset of regions implicated in this change. Interestingly, these regions correlate with in vivo density maps of serotonin receptors 5-HT2A and 5-HT1A, which psilocin, the active metabolite of psilocybin, has an appreciable affinity for, and where it acts as a full-to-partial agonist. Serotonergic transmission has long been associated with depression and our findings provide causal mechanistic evidence for the role of brain regions in the recovery from depression via psilocybin.

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“…Notably, these regions matched those with the highest density of 5HT 2a and 5HT 1a neuroreceptors. This relationship is plausible given that psilocin (psilocybin's active metabolite) is known to have an appreciable-to-high a nity for the 5-HT1A and 2A receptors, respectively, where it acts as an agonist; in the case of the 5-HT2AR, potentially stimulating plasticity-related signaling cascades relevant to an antidepressant action (52,53).…”

Section: Discussionmentioning

confidence: 99%

Brain dynamics predictive of response to psilocybin for treatment-resistant depression

Vohryzek

Cabral

Lord³

et al. 2022

Preprint

View full text Add to dashboard Cite

Psilocybin therapy for depression has started to show promise, yet the underlying causal mechanisms are not currently known. Here we leveraged the differential outcome in responders and non-responders to psilocybin (10mg and 25mg, 7 days apart) therapy for depression - to gain new insights into regions and networks implicated in the restoration of healthy brain dynamics. We used whole-brain modelling to fit the spatiotemporal brain dynamics at rest in both responders and non-responders before treatment. Dynamic sensitivity analysis of systematic perturbation of these models enabled us to identify specific brain regions implicated in a transition from a depressive brain state to a heathy one. Binarizing the sample into treatment responders (> 50% reduction in depressive symptoms) versus non-responders enabled us to identify a subset of regions implicated in this change. Interestingly, these regions correlate with in vivo density maps of serotonin receptors 5-HT2A and 5-HT1A, which psilocin, the active metabolite of psilocybin, has an appreciable affinity for, and where it acts as a full-to-partial agonist. Serotonergic transmission has long been associated with depression and our findings provide causal mechanistic evidence for the role of brain regions in the recovery from depression via psilocybin.

show abstract

Gs signaling pathway distinguishes hallucinogenic and nonhallucinogenic 5-HT2AR agonists induced head twitch response in mice

Cited by 20 publications

References 21 publications

Structure–Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice

Structure–Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice

Brain dynamics predictive of response to psilocybin for treatment-resistant depression

Brain dynamics predictive of response to psilocybin for treatment-resistant depression

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