Investigation of neuronal basis underlying antidepressant effect of serotonergic psychedelics
Proceedings for Annual Meeting of The Japanese Pharmacological Society 2022 DOI: 10.1254/jpssuppl.95.0_3-s35-1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study in mice Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | DOI psilocin CNO |
| Topics | Psilocybin Serotonin |
| Keywords | Pharmacology Antidepressant 5-HT Receptor Gabaergic Inhibitory postsynaptic potential |
| Key findings | Activation of 5-HT2A-positive GABAergic neurons in the lateral septum mediates the antidepressant effect of serotonergic psychedelics in mice. |
Abstract
Recently, FDA approved psilocybin, the psychoactive substance found in the magic mushroom, as a "breakthrough therapy" for depression; however, its detailed mechanism remains unknown. Serotonergic psychedelics such as psilocybin and LSD have hallucinatory effect through stimulation of serotonin 5-HT2A receptor (5-HT2A), motivating us to investigate the role of 5-HT2A stimulation in antidepressant effect of serotonergic psychedelics as well as its neural basis in mice. We demonstrated that 5-HT2A agonists such as DOI and psilocin, an active metabolite of psilocybin, decreased immobility time in the forced-swim test (FST), which was absent in mice with knockdown of Htr2a (5-HT2A gene) in the lateral septum (LS) by AAV-delivered shRNA. Since 5-HT2A is a Gq-coupled GPCR, we next investigated the effect of Gq signaling activation in 5-HT2A-positive neurons in LS on emotional behaviors in mice, for which hM3Dq, a Gq-coupled designer receptor activated by CNO, was transfected into 5-HT2A-positive neurons in LS of Htr2a-cre mice by microinjection of cre-dependent AAV. Activation of the hM3Dq with CNO induced antidepressant and anxiolytic effects in mice. Further, we found that most of 5-HT2A-positive cells in LS were the GABAergic inhibitory neurons, suggesting that activation of 5-HT2A-positive GABAergic neurons in LS leads to antidepressant effect. In this symposium, I would like to introduce the role of 5-HT2A in LS in not only antidepressant effect but also hallucination of serotonergic 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 |