Investigation of neuronal basis underlying antidepressant effect of serotonergic psychedelics

The FDA has approved psilocybin, the psychoactive compound in magic mushrooms, as a breakthrough therapy for depression, but its detailed mechanism remains unknown. Serotonergic psychedelics like psilocybin and LSD produce hallucinatory effects by stimulating the serotonin 5-HT2A receptor. In mice, 5-HT2A agonists such as DOI and psilocin (the active metabolite of psilocybin) reduced immobility time in the forced-swim test, an effect absent when the 5-HT2A gene was knocked down in the lateral septum. Activating Gq signaling in 5-HT2A-positive neurons in the lateral septum produced antidepressant and anxiolytic effects. Most 5-HT2A-positive cells in the lateral septum are GABAergic inhibitory neurons, suggesting their activation underlies the antidepressant effect.

Study at a glance

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.