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Effects of a psychedelic 5-HT2A receptor agonist on anxiety-related behavior and fear processing in mice.

Błażej D. Pędzich, Sarah Rubens, Mehdi Sekssaoui, Anouk Pierre, Andries Van Schuerbeek, Philippe Marin, Joël Bockaert, Emmanuel Valjent, Carine Bécamel, Dimitri de Bundel

Neuropsychopharmacology June 1, 2022 DOI: 10.1038/s41386-022-01324-2 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Experimental study Peer reviewed
Population 5-HT2A receptor knockout and wild-type mice
Interventions 2 5-dimethoxy-4-iodoamphetamine (DOI) M100907
Topics Anxiety Serotonin
Key findings Activation of 5-HT2A receptors in the amygdala suppresses fear expression but does not affect retention of fear extinction.

Abstract

Psychedelic-assisted psychotherapy gained considerable interest as a novel treatment strategy for fear-related mental disorders but the underlying mechanism remains poorly understood. The serotonin 2A (5-HT2A) receptor is a key target underlying the effects of psychedelics on emotional arousal but its role in fear processing remains controversial. Using the psychedelic 5-HT2A/5-HT2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and 5-HT2A receptor knockout (KO) mice we investigated the effect of 5-HT2A receptor activation on emotional processing. We show that DOI administration did not impair performance in a spontaneous alternation task but reduced anxiety-like avoidance behavior in the elevated plus maze and elevated zero maze tasks. Moreover, we found that DOI did not block memory recall but diminished fear expression in a passive avoidance task. Likewise, DOI administration reduced fear expression in an auditory fear conditioning paradigm, while it did not affect retention of fear extinction when administered prior to extinction learning. The effect of DOI on fear expression was abolished in 5-HT2A receptor KO mice. Administration of DOI induced a significant increase of c-Fos expression in specific amygdalar nuclei. Moreover, local infusion of the 5-HT2A receptor antagonist M100907 into the amygdala reversed the effect of systemic administration of DOI on fear expression while local administration of DOI into the amygdala was sufficient to suppress fear expression. Our data demonstrate that activation of 5-HT2A receptors in the amygdala suppresses fear expression but provide no evidence for an effect on retention of fear extinction.

Comparable studies

Other preclinical and animal studies on serotonin, most cited first.

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Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) 1987 Experimental study
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3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain 1987 Animal experiment
Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells 2006 In vitro laboratory study

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Anxiety Serotonin Addiction Psychedelic-assisted therapy