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Psychedelic-Induced Serotonin 2A Receptor Downregulation Does Not Predict Swim Stress Coping in Mice

Mireia Medrano, An Buckinx, Ilse Smolders, Błażej D. Pędzich, Dimitri de Bundel

International Journal of Molecular Sciences December 4, 2022 DOI: 10.3390/ijms232315284 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Animal experiment Peer reviewed
Population Mice
Interventions 2 5-dimethoxy-4-iodoamphetamine (DOI)
Dose 0.2 mg/kg i.p. and 2 mg/kg i.p.
Duration 6 days between swim stress and forced swim test; DOI administered 1 day before forced swim test
Topics Psilocybin Serotonin
Keywords Behavioural despair test 5-ht1a receptor 5-HT Receptor Prefrontal cortex Downregulation and upregulation Endocrinology Antidepressant Hallucinogen
Citations 11
Key findings Downregulation of 5-HT2A receptors in the medial prefrontal cortex does not appear to contribute to antidepressant-like effects of serotoninergic psychedelics.

Abstract

Serotoninergic psychedelics such as psilocybin have been reported to elicit a long-lasting reduction in depressive symptoms. Although the main target for serotoninergic psychedelics, serotonin type 2A receptor (5-HT2A), has been established, the possible mechanism of the antidepressant action of psychedelics remains unknown. Using the mouse forced swim test model, we examined whether the administration of the synthetic serotoninergic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) would modulate 5-HT2A receptor levels in the medial prefrontal cortex (mPFC) and revert stress-induced changes in behavior. Mice subjected to swim stress developed a passive stress-coping strategy when tested in the forced swim test 6 days later. This change in behavior was not associated with the hypothesized increase in 5-HT2A receptor-dependent head twitch behaviors or consistent changes in 5-HT2A receptor levels in the mPFC. When DOI was administered 1 day before the forced swim test, a low dose (0.2 mg/kg i.p.) unexpectedly increased immobility while a high dose (2 mg/kg i.p.) had no significant effect on immobility. Nevertheless, DOI evoked a dose-dependent decrease in 5-HT2A levels in the mPFC of mice previously exposed to swim stress. Our findings do not support the hypothesis that the downregulation of 5-HT2A receptors in the mPFC contributes to the antidepressant-like properties of serotoninergic psychedelics.

Comparable studies

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

Study Year Design Participants
Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice 2021 Observational cohort
Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) 1987 Experimental study
Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models 2023 Experimental study
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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