Investigation of neuronal basis underlying antidepressant effect of serotonergic psychedelics
Proceedings for Annual Meeting of The Japanese Pharmacological Society – January 01, 2022
Source: OpenAlex
Summary
Psilocybin's antidepressant pharmacology, a key area in psychedelics and drug studies, is now clearer. Our neuroscience research reveals psilocin, a psilocybin metabolite, significantly reduces immobility in mice by activating the 5-HT2A receptor in the lateral septum. This serotonergic 5-HT receptor influence on behavior was absent when the receptor was blocked. Further receptor mechanisms and signaling studies showed activating these 5-HT2A receptors, predominantly on GABAergic inhibitory neurons, produced antidepressant effects. This chemistry suggests neurotransmitter receptor influence on behavior via these specific inhibitory pathways.
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.