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Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action - PubMed

  • ️Sun Jan 01 2023

Review

Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action

Lindsay P Cameron et al. J Neurosci. 2023.

Abstract

Serotonergic psychedelics, such as psilocybin and LSD, have garnered significant attention in recent years for their potential therapeutic effects and unique mechanisms of action. These compounds exert their primary effects through activating serotonin 5-HT2A receptors, found predominantly in cortical regions. By interacting with these receptors, serotonergic psychedelics induce alterations in perception, cognition, and emotions, leading to the characteristic psychedelic experience. One of the most crucial aspects of serotonergic psychedelics is their ability to promote neuroplasticity, the formation of new neural connections, and rewire neuronal networks. This neuroplasticity is believed to underlie their therapeutic potential for various mental health conditions, including depression, anxiety, and substance use disorders. In this mini-review, we will discuss how the 5-HT2A receptor activation is just one facet of the complex mechanisms of action of serotonergic psychedelics. They also interact with other serotonin receptor subtypes, such as 5-HT1A and 5-HT2C receptors, and with neurotrophin receptors (e.g., tropomyosin receptor kinase B). These interactions contribute to the complexity of their effects on perception, mood, and cognition. Moreover, as psychedelic research advances, there is an increasing interest in developing nonhallucinogenic derivatives of these drugs to create safer and more targeted medications for psychiatric disorders by removing the hallucinogenic properties while retaining the potential therapeutic benefits. These nonhallucinogenic derivatives would offer patients therapeutic advantages without the intense psychedelic experience, potentially reducing the risks of adverse reactions. Finally, we discuss the potential of psychedelics as substrates for post-translational modification of proteins as part of their mechanism of action.

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Figures

Figure 1.
Figure 1.

The multiple targets of serotonergic psychedelic drugs. Among the major anatomic targets for serotonergic psychedelics are cortical areas, such as the PFC, where serotonergic receptors are located in pyramidal neurons. Although activation of 5-HT2A receptors is an integral element of the hallucinogenic experience and may contribute to some of the proposed therapeutic effects of these class of drugs, other receptors of the same family (5-HT2C and 5-HT1A) or even the TrkB receptor of the neurotrophin, BDNFs are involved in the therapeutic effects of psychedelic drugs. This suggests a potential to dissociate psychedelics from therapeutic effects. a, Several psychedelic drugs may also induce their effects (psychedelic and or therapeutic) via a biased activation of signaling pathways (G-protein-mediated vs β-arrestin). b, Alternatively, serotonergic psychedelics may target intracellular 5-HT2A receptors to induce therapeutic effects because of their lipophilicity, which allows them to traverse the cell membrane. c, Some derivatives, such as 2-Br-LSD, also target 5-HT2A receptors as partial agonists, inducing synaptic plasticity but lacking hallucinogenic effects. d, Finally, it is also conceivable that several psychedelics and entactogens can be a substrate for TGM2 to monoamylate glutamine restudies in proteins, such as Rac1 or histones, to alter cytoskeleton function or gene expression, respectively, in the induction of lasting therapeutic effects.

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