Neurochemical and behavioural characterisation of the psychedelic 5HT2AR agonist psilocybin in mice

Resetting the Hippocampal Buffer: A Neurocognitive Account of Psychedelic Therapy for Anxiety-Related Psychopathology

“…In humans, whereas psilocybin-induced increases in prefrontal glutamate were associated with anxious ego dissolution (the loss of one's sense of self), psilocybin decreased hippocampal glutamate, which was associated with positively experienced ego dissolution (Mason et al, 2020). This model would also predict that tryptamine psychedelics may be better-suited for treating anxiety-related psychopathology, given that they may more readily increase hippocampal neurogenesis (Banasr et al, 2004;Catlow et al, 2013;Jha et al, 2008;Lima Da Cruz et al, 2018;Morales-Garcia et al, 2020) and bind to 5-HT1ARs (Erkizia-Santamaría et al, 2022;Rickli et al, 2015), with 5-HT1AR activation known to attenuate anxiety (Inoue et al, 2011;Toth, 2003) and being itself associated with hippocampal neurogenesis (Gould, 1999;Grabiec et al, 2009). Finally, there is the issue of proper dosing.…”

“…As discussed, while these receptors are most densely found in the cortex, especially on (excitatory) pyramidal neurons (Aghajanian & Marek, 1997;Beliveau et al, 2017;Jakab & Goldman-Rakic, 1998;Martin & Nichols, 2016), they are also found in the hippocampus, the input to the hippocampus (i.e., entorhinal cortex), and the amygdala, largely on (inhibitory) interneurons (Bombardi, 2012;Bombardi & Di Giovanni, 2013;de Filippo et al, 2021;Deng & Lei, 2008;Jiang et al, 2009;Kelly et al, 2023;Lüttgen et al, 2004;Shen & Andrade, 1998;Wyskiel & Andrade, 2016). Most psychedelics also activate other 5-HT receptors, with psychedelic tryptamines such as psilocybin and DMT more prominently activating 5-HT1ARs than psychedelic phenethylamines such as mescaline (Erkizia-Santamaría et al, 2022;Rickli et al, 2015).…”

Molecular insights into the modulation of the 5HT2Areceptor by serotonin, psilocin, and the G protein subunit Gqα

“…Our discoveries can inform the design of new pharmaceuticals that target specific receptor conformations, potentially leading to more effective treatments for mental disorders.Due to the comparatively non-specific binding mode, many psychedelics like LSD and psilocin act promiscuously on many neural receptors. 5 Besides 5HT 2A R, psilocin, and synthetic psilocin analogs exhibit binding affinities for 5HT 1A R and 5HT 2C R [12][13][14] and animal studies suggest that psilocin unfolds its psychedelic and antidepressant effects not solely via stimulation of 5HT 2A R. [15][16][17] The structure of 5HT 2C R in complex with psilocin shows that psilocin is similarly anchored in the orthosteric binding pocket (OBP) via the conserved central D1343.32 residue, and the indole core is coordinated through interactions with additional residues in the OBP. 18 Moreover, psychedelics like ketamine, LSD, and psilocin influence synaptic plasticity, thereby facilitating antidepressant effects by binding to the neurotrophic tyrosine kinase receptor 2 (TrkB) and stimulating endogenous brain-derived neurotrophic factor (BDNF) signaling.…”

“…Due to the comparatively non-specific binding mode, many psychedelics like LSD and psilocin act promiscuously on many neural receptors. 5 Besides 5HT 2A R, psilocin, and synthetic psilocin analogs exhibit binding affinities for 5HT 1A R and 5HT 2C R [12][13][14] and animal studies suggest that psilocin unfolds its psychedelic and antidepressant effects not solely via stimulation of 5HT 2A R. [15][16][17] The structure of 5HT 2C R in complex with psilocin shows that psilocin is similarly anchored in the orthosteric binding pocket (OBP) via the conserved central D134…”