Investigation of the neural network responsible for antidepressant effect of serotonergic psychedelics

Psilocin, the active metabolite of psilocybin, produces antidepressant effects in mice by activating serotonin 5-HT2A receptors on GABAergic neurons in the lateral septum that project to the dorsomedial hypothalamic nucleus. Selectively inhibiting this pathway eliminated the antidepressant-like effect in forced-swim and social defeat stress tests, while activating it induced antidepressant-like effects. Microinjection of bicuculline, a GABAA receptor antagonist, into the dorsomedial hypothalamic nucleus diminished psilocin's antidepressant effect. These findings suggest that this specific neural network underlies the antidepressant action of serotonergic psychedelics, separate from their hallucinatory effects mediated by the visual cortex.

Study at a glance

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.