Sigma-1 (σ1) receptor activity is necessary for physiological brain plasticity in mice

Crouzier, Lucie; Couly, Simon; Roques, Chloé; Peter, Claude; Belkhiter, Rislen; Jacquemin, Maëva Arguel; Bonetto, Anna; Delprat, Benjamin; Maurice, Tangui

doi:10.1016/j.euroneuro.2020.08.010

Cited by 22 publications

(13 citation statements)

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“…In addition to 5-HT 2A receptors, the effects on neurogenesis seen with DMT and 5-MeO-DMT could potentially involve other receptors [ 42 , 43 ]. DMT has low but functionally significant affinity for the sigma-1 receptor, an orphan receptor involved in neuroprotection and neurogenesis [ 78 ]. Sigma-1 receptor antagonists block DMT’s effects on hippocampal neurogenesis [ 44 , 79 ], and sigma-1 receptor activity has also been shown to stimulate neurogenesis in previous studies [ 80 – 82 ].…”

Section: How Do Psychedelics Enhance Neuroplasticity?mentioning

confidence: 99%

Towards an understanding of psychedelic-induced neuroplasticity

Calder

Hasler

2022

Neuropsychopharmacol.

140

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Classic psychedelics, such as LSD, psilocybin, and the DMT-containing beverage ayahuasca, show some potential to treat depression, anxiety, and addiction. Importantly, clinical improvements can last for months or years after treatment. It has been theorized that these long-term improvements arise because psychedelics rapidly and lastingly stimulate neuroplasticity. The focus of this review is on answering specific questions about the effects of psychedelics on neuroplasticity. Firstly, we review the evidence that psychedelics promote neuroplasticity and examine the cellular and molecular mechanisms behind the effects of different psychedelics on different aspects of neuroplasticity, including dendritogenesis, synaptogenesis, neurogenesis, and expression of plasticity-related genes (e.g., brain-derived neurotrophic factor and immediate early genes). We then examine where in the brain psychedelics promote neuroplasticity, particularly discussing the prefrontal cortex and hippocampus. We also examine what doses are required to produce this effect (e.g., hallucinogenic doses vs. “microdoses”), and how long purported changes in neuroplasticity last. Finally, we discuss the likely consequences of psychedelics’ effects on neuroplasticity for both patients and healthy people, and we identify important research questions that would further scientific understanding of psychedelics’ effects on neuroplasticity and its potential clinical applications.

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Section: How Do Psychedelics Enhance Neuroplasticity?mentioning

confidence: 99%

Towards an understanding of psychedelic-induced neuroplasticity

Calder

Hasler

2022

Neuropsychopharmacol.

140

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“…The two compounds stand out as candidates for interrogating previously proposed interplay between 5-HT and σ receptors to induce neuroplasticity. 38,39 While both drug molecules reveal comparable affinities at σ receptors, 4-HO-NBnT distinctively exhibits high affinity and activity at 5-HT receptors, while 4-HO-NcHT does not. This suggests a congruent binding modality for both compounds at σ receptors, while differing substantially in their interactions at 5-HT receptors.…”

Section: Head Twitch Response Studiesmentioning

confidence: 99%

Psychedelic-like Activity of Norpsilocin Analogues

Sherwood,

Burkhartzmeyer,

Williamson

et al. 2024

ACS Chem. Neurosci.

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Primary metabolites of mushroom tryptamines, psilocybin and baeocystin (i.e., psilocin and norpsilocin), exhibit potent agonist activity at the serotonin 2A receptor (5-HT 2A ) in vitro but differ in their 5-HT 2A -mediated effects in vivo. In particular, psilocin produces centrally mediated psychedelic effects in vivo, whereas norpsilocin, differing only by the loss of an N-methyl group, is devoid of psychedelic-like effects. These observations suggest that the secondary methylamine group in norpsilocin impacts its central nervous system (CNS) bioavailability but not its receptor pharmacodynamics. To test this hypothesis, eight norpsilocin derivatives were synthesized with varied secondary alkyl-, allyl-, and benzylamine groups, primarily aiming to increase their lipophilicity and brain permeability. Structure−activity relationships for the norpsilocin analogues were evaluated using the mouse head-twitch response (HTR) as a proxy for CNS-mediated psychedelic-like effects. HTR studies revealed that extending the N-methyl group of norpsilocin by a single methyl group, to give the corresponding secondary N-ethyl analogue (4-HO-NET), was sufficient to produce psilocin-like activity (median effective dose or ED 50 = 1.4 mg/kg). Notably, N-allyl, N-propyl, N-isopropyl, and N-benzyl derivatives also induced psilocin-like HTR activity (ED 50 = 1.1−3.2 mg/kg), with variable maximum effects (26−77 total HTR events). By contrast, adding bulkier tert-butyl or cyclohexyl groups in the same position did not elicit psilocin-like HTRs. Pharmacological assessments of the tryptamine series in vitro demonstrated interactions with multiple serotonin receptor subtypes, including 5-HT 2A , and other CNS signaling proteins (e.g., sigma receptors). Overall, our data highlight key structural requirements for CNS-mediated psychedelic-like effects of norpsilocin analogues.

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“…On the other hand, sigma-1 knockout male and female mice had impaired long-term, but not short-term, recognition memory ( Xu et al, 2017 ). Also, the Hamlet test, where animals are exposed to an enriched environment, showed that lack of sigma-1 receptors completely prevented the establishment of topographic memory and behavioral resilience, as well as the hippocampal neurogenesis ( Crouzier et al, 2020 ). These differences between males and females suggest that sex hormones may affect sigma-1 receptors signaling and in consequence memory processes.…”

Section: Memory Functioning and Sigma-1 Receptorsmentioning

confidence: 99%