Ippolito, A. | Search bioRxiv

bioRxiv2024

Increased 5-HT2A receptor signalling efficacy differentiates serotonergic psychedelics from non-psychedelics

Background and PurposeSerotonergic psychedelic drugs are under renewed investigation for the potential treatment of several psychiatric disorders. While all serotonergic psychedelics have 5-HT2A receptor activity, the explanation for why some 5-HT2A receptor agonists are not psychedelic is unknown. To address this question, we investigated the 5-HT2A receptor signalling bias and efficacy of a panel of psychedelics and non-psychedelics. Experimental ApproachG -coupled (Ca2+ and IP) and {beta}-arrestin2 signalling effects of eight chemically diverse psychedelics (psilocin, 5-MeO-DMT, LSD, mescaline, 25B-NBOMe and DOI) and non-psychedelics (lisuride and TBG) were characterised using SH-SY5Y cells expressing recombinant human 5-HT2A receptors. Measurements of signalling efficacy and bias were derived from dose-responses curves for each agonist, compared to 5-HT. Follow-up experiments sought to confirm the generality of findings using rat C6 cells expressing endogenous 5-HT2A receptors. Key ResultsIn SH-SY5Y cells, all psychedelics were partial agonists at both 5-HT2A receptor signalling pathways and none showed significant signalling bias. In comparison, in SH-SY5Y cells the non-psychedelics lisuride and TBG were not distinguishable from psychedelics in terms of biased agonist properties, but both exhibited the lowest 5-HT2A receptor signalling efficacy of all drugs tested, a result confirmed in C6 cells. Conclusion and ImplicationsIn summary, all psychedelics tested were unbiased, partial 5-HT2A receptor agonists. Importantly, the non-psychedelics lisuride and TBG were discriminated from psychedelics, not through biased signalling but rather by relatively low efficacy. Thus, 5-HT2A receptor signalling efficacy and not bias provides a possible explanation for why some 5-HT2A receptor agonists are not psychedelic.

pharmacology and toxicology↗

bioRxiv2021

Contact guidance as a consequence of coupled morphological evolution and motility of adherent cells

Adherent cells seeded on substrates spread and evolve their morphology while simultaneously displaying motility. Phenomena such as contact guidance viz. the alignment of cells on patterned substrates, are strongly linked to the coupling of morphological evolution with motility. Here we employ a recently developed statistical thermodynamics framework for modelling the non-thermal fluctuating response of the cells to probe this coupling. This thermodynamic framework is first extended to predict temporal responses via a Langevin style model. The Langevin model is then shown to not only predict the different experimentally observed temporal scales for morphological observables such as cell area and elongation but also the interplay of morphology with motility that ultimately leads to contact guidance. Author SummaryThe evolution of cellular morphology and organization plays a crucial role in the micro-architecture of tissues and dictates their biological and mechanical functioning. Despite the importance of cellular organization in all facets of tissue biology, the fundamental question of how a cell organizes itself in an anisotropic environment is still poorly understood. We demonstrate, using a Langevin style model, that non-thermal fluctuations fuelled by nutrient exchanges between the cell and its environment are critical in allowing cells to explore their surroundings. The biochemical changes, associated with non-thermal fluctuations, drive cell motility and morphological changes and the interplay between these two emerging dynamics ultimately leads to contact guidance, a critical component for tissue morphogenesis.

biophysics↗