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Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD.

ABSTRACT: Serotonin (5-hydroxytryptamine [5-HT]) 5-HT2-family receptors represent essential targets for lysergic acid diethylamide (LSD) and all other psychedelic drugs. Although the primary psychedelic drug effects are mediated by the 5-HT_2A serotonin receptor (HTR2A), the 5-HT_2B serotonin receptor (HTR2B) has been used as a model receptor to study the activation mechanisms of psychedelic drugs due to its high expression and similarity to HTR2A. In this study, we determined the cryo-EM structures of LSD-bound HTR2B in the transducer-free, Gq-protein-coupled, and β-arrestin-1-coupled states. These structures provide distinct signaling snapshots of LSD's action, ranging from the transducer-free, partially active state to the transducer-coupled, fully active states. Insights from this study will both provide comprehensive molecular insights into the signaling mechanisms of the prototypical psychedelic LSD and accelerate the discovery of novel psychedelic drugs.

SUBMITTER: Cao C

PROVIDER: S-EPMC9583076 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD.

Cao Can C Barros-Álvarez Ximena X Zhang Shicheng S Kim Kuglae K Dämgen Marc A MA Panova Ouliana O Suomivuori Carl-Mikael CM Fay Jonathan F JF Zhong Xiaofang X Krumm Brian E BE Gumpper Ryan H RH Seven Alpay B AB Robertson Michael J MJ Krogan Nevan J NJ Hüttenhain Ruth R Nichols David E DE Dror Ron O RO Skiniotis Georgios G Roth Bryan L BL

Neuron 20220909 19

Serotonin (5-hydroxytryptamine [5-HT]) 5-HT2-family receptors represent essential targets for lysergic acid diethylamide (LSD) and all other psychedelic drugs. Although the primary psychedelic drug effects are mediated by the 5-HT<sub>2A</sub> serotonin receptor (HTR2A), the 5-HT<sub>2B</sub> serotonin receptor (HTR2B) has been used as a model receptor to study the activation mechanisms of psychedelic drugs due to its high expression and similarity to HTR2A. In this study, we determined the cryo ...[more]

PMID: 36087581

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Project description:Rationale: Stimulation of serotonin 2A (5-HT2A) receptors by lysergic acid diethylamide (LSD) and related compounds such as psilocybin has previously been shown to increase primary process thinking - an ontologically and evolutionary early, implicit, associative, and automatic mode of thinking which is typically occurring during altered states of consciousness such as dreaming. However, it is still largely unknown whether LSD induces primary process thinking under placebo-controlled, standardized experimental conditions and whether these effects are related to subjective experience and 5-HT2A receptor activation. Therefore, this study aimed to test the hypotheses that LSD increases primary process thinking and that primary process thinking depends on 5-HT2A receptor activation and is related to subjective drug effects. Methods: Twenty-five healthy subjects performed an audio-recorded mental imagery task 7 h after drug administration during three drug conditions: placebo, LSD (100 mcg orally) and LSD together with the 5-HT2A receptor antagonist ketanserin (40 mg orally). The main outcome variable in this study was primary index (PI), a formal measure of primary process thinking in the imagery reports. State of consciousness was evaluated using the Altered State of Consciousness (5D-ASC) rating scale. Results: LSD, compared with placebo, significantly increased primary index (p < 0.001, Bonferroni-corrected). The LSD-induced increase in primary index was positively correlated with LSD-induced disembodiment (p < 0.05, Bonferroni-corrected), and blissful state (p < 0.05, Bonferroni-corrected) on the 5D-ASC. Both LSD-induced increases in primary index and changes in state of consciousness were fully blocked by ketanserin. Conclusion: LSD induces primary process thinking via activation of 5-HT2A receptors and in relation to disembodiment and blissful state. Primary process thinking appears to crucially organize inner experiences during both dreams and psychedelic states of consciousness.

Dataset Information

Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD.

Publications

Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD.

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