Investigation of the neural network responsible for antidepressant effect of serotonergic psychedelics
Proceedings for Annual Meeting of The Japanese Pharmacological Society 2022 DOI: 10.1254/jpssuppl.96.0_4-b-s43-2 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with optogenetic and chemogenetic approaches Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | psilocin bicuculline |
| Topics | Psilocybin Serotonin |
| Keywords | Antidepressant Pharmacology Stimulation Gabaergic Bicuculline Gabaa receptor |
| Key findings | The 5-HT2A-positive lateral septum to dorsomedial hypothalamic nucleus GABAergic pathway is responsible for the antidepressant-like effect of psilocin in mice. |
Abstract
Serotonergic psychedelics such as psilocybin, the psychoactive substance found in the magic mushroom, have hallucinatory effect through stimulation of the cortical serotonin 5-HT2A receptor (5-HT2A). Recently, FDA has called psilocybin a 'breakthrough therapy' for severe depression. We have already demonstrated that 5-HT2A in the lateral septum (LS) plays a responsible role in antidepressant-like effect of psilocin, an active metabolite of psilocybin, whereas hallucinatory effect of psilocin was attributed to 5-HT2A stimulation in the visual cortex (V1) in mice. Here, we investigated the neural network responsible for antidepressant effect of psilocin. The histological study with anterograde and retrograde transports of adeno-associated viruses showed that 5-HT2A in LS abundantly expressed in GABAergic neurons, which projects to the dorsomedial hypothalamic nucleus (DM) in mice. Therefore, we investigated the functional role of 5-HT2A-positive LS-DM pathway in antidepressant effect by optogenetic and chemogenetic approaches. Selective inhibition of 5-HT2A-positive LS-DM pathway eliminated the antidepressant-like effect of psilocin in mice in forced-swim test as well as social defeat stress test. On the other hand, activation of the LS-DM pathway induced antidepressant-like effect in mice. Lastly, microinjection of bicuculline, an antagonist of GABAA receptor, into the DM diminished such effect of psilocin in mice. These suggest that 5-HT2A-positive LS-DM GABAergic network contributes to antidepressant effect 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 |