Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action

Abstract

Recent, well-controlled - albeit small-scale - clinical trials show that serotonergic psychedelics, including psilocybin and lysergic acid diethylamide, possess great promise for treating psychiatric disorders, including treatment-resistant depression. Additionally, fresh results from a deluge of clinical neuroimaging studies are unveiling the dynamic effects of serotonergic psychedelics on functional activity within, and connectivity across, discrete neural systems. These observations have led to testable hypotheses regarding neural processing mechanisms that contribute to psychedelic effects and therapeutic benefits. Despite these advances and a plethora of preclinical and clinical observations supporting a central role for brain serotonin 5-HT receptors in producing serotonergic psychedelic effects, lingering and new questions about mechanisms abound. These chiefly pertain to molecular neuropharmacology. This chapter is devoted to illuminating and discussing such questions in the context of preclinical experimental approaches for studying mechanisms of action of serotonergic psychedelics, classic and new.

In vitro structure–activity relationship determination of 30 psychedelic new psychoactive substances by means of β-arrestin 2 recruitment to the serotonin 2A receptor

“…With the more recent group of NBOMes, a number of case reports requiring hospitalization, suicide attempts and even deaths have been reported (Hondebrink et al 2018;Kyriakou et al 2015;Luethi and Liechti 2020;Suzuki et al 2015). Furthermore, a mass poisoning has been reported with Bromo-DragonFLY and 2C-E (Iwersen-Bergmann et al 2019) The main pharmacological target of serotonergic psychedelics, the 5-HT2AR, is a G protein-coupled receptor (GPCR) (Canal 2018;Nichols 2004). Activation of the 5-HT2AR induces an interaction of the receptor with the G protein, in this particular case Gαq.…”

The Therapeutic Potential of Psilocybin

“…Mystical-type experience, which predicted the success of the therapy and likelihood of persisting positive benefits [ 9 , 15 ],…”

“…Classic psychedelic (serotonergic) drugs interact with the serotonin receptors (5-HT/5-hydroxytryptamine receptors) and their subtypes densely located within the brain [ 7 , 8 , 9 ]. These receptors mediate emotions and moods such as anxiety and aggression, cognition, sex, learning memory, appetite along with other biological, neurological and neuropsychiatric processes [ 8 , 10 ].…”

Changing the Cortical Conductor’s Tempo: Neuromodulation of the Claustrum

“…From an evolutionary perspective, 5-HT is one of the oldest neuromodulators (Peroutka, 1995 ). In the mammalian brain, 5-HT is involved in a diverse range of processes, including sleep (Jouvet, 1999 ; Monti, 2010 ), learning and memory (Meneses, 2015 ; Zhang and Stackman, 2015 ), emotions (Altieri et al, 2013 ; Aznar and Klein, 2013 ; Bauer, 2015 ) and psychedelic drug action (Nichols, 2016 ; Canal, 2018 ). Although many of these processes overlap with the functions proposed for the claustrum, until recently serotonergic modulation of the claustrum was largely ignored.…”

“…Subsequent work identified the 5-HTR types that are present in the claustrum. These studies employed 5-HTR agonist and antagonist radioligands (e.g., ketanserin); one caveat of such analyses is the known off-target effects of these agents (Aloyo and Harvey, 2000 ; Canal, 2018 ). The consistent conclusion of such studies is that 5-HTR-2A and 5-HTR-2C are highly expressed in the claustrum of several species (Dawson et al, 1986 ; Mengod et al, 1990 ; Pompeiano et al, 1994 ; Wright et al, 1995 ; Ward and Dorsa, 1996 ; Hamada et al, 1998 ; Rioux et al, 1999 ; Kinsey et al, 2001 ; Olaghere da Silva et al, 2010 ; Gawliński et al, 2019 ).…”