Serotonin 5-HT2A, 5-HT2c and 5-HT1A receptor involvement in the acute effects of psilocybin in mice. In vitro pharmacological profile and modulation of thermoregulation and head-twich response

Erkizia-Santamaría, I.; Alles-Pascual, R.; Horrillo, I.; Meana, J.J.; Ortega, J.E.

doi:10.1016/j.biopha.2022.113612

Cited by 35 publications

(25 citation statements)

References 63 publications

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“…For example, 5-HT 1A agonist pretreatment reduces 5-HT 2A -mediated effects of psychedelics in rodents and humans, while 5-HT 1A antagonists have the opposite effect. ,− Here, we show that secondary and tertiary amine psilocybin analogues produce 5-HT 1A -mediated suppression of locomotor activity and body temperature. These effects are consistent with other studies showing similar effects of psilocybin and psilocin at high doses in rodents that were reversed by 5-HT 1A antagonist pretreatment. , In the case of tertiary amines, the induction of 5-HT 1A effects in vivo required ∼10-fold higher doses than those eliciting 5-HT 2A -mediated HTR. In fact, the descending limb of the HTR dose–response curve for all drugs coincided with the expression of 5-HT 1A -mediated hypolocomotion and hypothermia, suggesting that 5-HT 1A activation counteracted HTR.…”

Section: Discussionsupporting

confidence: 91%

“…The HTR produced by tertiary amines was completely blocked by pretreatment with the 5-HT 2A antagonist M100907. Our in vivo findings with psilocybin and psilocin agree with previous results showing that these compounds, and related N , N -disubstituted tryptamines, induce HTR in mice. ,,,, It is noteworthy that ED 50 potency values reported here for psilocybin (i.e., 0.29 mg/kg, s.c.) and psilocin (i.e., 0.11 mg/kg, s.c.) to induce HTR are nearly identical to those reported by others who used magnetometer-based scoring methods to quantify HTR. ,, It is not surprising that quaternary ammoniums failed to induce HTR because these compounds display weak or no affinity for 5-HT 2A . By contrast, the secondary amines norpsilocin and 4-AcO-NMT are potent agonists at 5-HT 2A in vitro , yet they did not induce HTR at any dose tested.…”

Section: Discussionsupporting

confidence: 91%

“…4-Hydroxy and 4-acetoxy compounds displayed higher affinities across all 5-HT receptors when compared to their 4-phosphoryloxy counterparts. Notably, our binding data agree with previous studies showing that psilocin is a nonselective 5-HT receptor ligand. , Drug binding affinities at human 5-HT 2A and 5-HT 1A in transfected cells were subsequently verified in native tissue preparations using radioligand binding assays in mouse brain membranes consistent with another recent study . The present studies also determined the potency and efficacy of psilocybin analogues for 5-HT 2A -mediated calcium mobilization and β-arrestin 2 recruitment in vitro .…”

Section: Discussionsupporting

confidence: 90%

“…Our in vivo findings with psilocybin and psilocin agree with previous results showing that these compounds, and related N,N-disubstituted tryptamines, induce HTR in mice. 23,40,41,55,59 It is noteworthy that ED 50 potency values reported here for psilocybin (i.e., 0.29 mg/kg, s.c.) and psilocin (i.e., 0.11 mg/kg, s.c.) to induce HTR are nearly identical to those reported by others who used magnetometerbased scoring methods to quantify HTR. 40,55,83 It is not surprising that quaternary ammoniums failed to induce HTR because these compounds display weak or no affinity for 5-HT 2A .…”

Section: ■ Discussionmentioning

confidence: 67%

“…26,58 Drug binding affinities at human 5-HT 2A and 5-HT 1A in transfected cells were subsequently verified in native tissue preparations using radioligand binding assays in mouse brain membranes consistent with another recent study. 59 The present studies also determined the potency and efficacy of psilocybin analogues for 5-HT 2Amediated calcium mobilization and β-arrestin 2 recruitment in vitro. Importantly, the rank order of drug potencies in the 5-HT 2A functional assays was similar to the rank order of affinities in 5-HT 2A binding at human and mouse receptors.…”

Section: ■ Discussionmentioning

confidence: 88%

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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: 91%

Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Section: ■ Discussionmentioning

confidence: 67%

Section: ■ Discussionmentioning

confidence: 88%

See 3 more Smart Citations

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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Assessment of the Acute Effects of 2C‐B vs. Psilocybin on Subjective Experience, Mood, and Cognition

Mallaroni

Mason

Reckweg

et al. 2023

Clin Pharma and Therapeutics

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2,5‐dimethoxy‐4‐bromophenethylamine (2C‐B) is a hallucinogenic phenethylamine derived from mescaline. Observational and preclinical data have suggested it to be capable of producing both subjective and emotional effects on par with other classical psychedelics and entactogens. Whereas it is the most prevalently used novel serotonergic hallucinogen to date, it's acute effects and distinctions from classical progenitors have yet to be characterized in a controlled study. We assessed for the first time the immediate acute subjective, cognitive, and cardiovascular effects of 2C‐B (20 mg) in comparison to psilocybin (15 mg) and placebo in a within‐subjects, double‐blind, placebo‐controlled study of 22 healthy psychedelic‐experienced participants. 2C‐B elicited alterations of waking consciousness of a psychedelic nature, with dysphoria, subjective impairment, auditory alterations, and affective elements of ego dissolution largest under psilocybin. Participants demonstrated equivalent psychomotor slowing and spatial memory impairments under either compound compared with placebo, as indexed by the Digit Symbol Substitution Test, Tower of London, and Spatial Memory Task. Neither compound produced empathogenic effects on the Multifaceted Empathy Test. 2C‐B induced transient pressor effects to a similar degree as psilocybin. The duration of self‐reported effects of 2C‐B was shorter than that of psilocybin, largely resolving within 6 hours. Present findings support the categorization of 2C‐B as a psychedelic of moderate experiential depth at doses given. Tailored dose‐effect studies are needed to discern the pharmacokinetic dependency of 2C‐B's experiential overlaps.

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Ethopharmacological evaluation of antidepressant-like effect of serotonergic psychedelics in C57BL/6J male mice

Takaba,

Ibi,

Yoshida

et al. 2023

Naunyn-Schmiedeberg's Arch Pharmacol

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Serotonin 5-HT2A, 5-HT2c and 5-HT1A receptor involvement in the acute effects of psilocybin in mice. In vitro pharmacological profile and modulation of thermoregulation and head-twich response

Cited by 35 publications

References 63 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

Assessment of the Acute Effects of 2C‐B vs. Psilocybin on Subjective Experience, Mood, and Cognition

Ethopharmacological evaluation of antidepressant-like effect of serotonergic psychedelics in C57BL/6J male mice

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