Antidepressant-like effects of psychedelics in a chronic despair mouse model: is the 5-HT2A receptor the unique player?

A single injection of psychedelic or non-hallucinogenic drugs that activate the serotonin 5-HT2A receptor can produce antidepressant- and anxiety-reducing effects in mice with a depression-like condition, lasting up to 15 days. The non-hallucinogenic drug lisuride was effective, suggesting hallucinogenic properties are not required for antidepressant action. In mice lacking the 5-HT2A receptor, the psychedelic DOI was ineffective, but psilocybin still worked, indicating psilocybin's effects can occur through other mechanisms. Blocking other serotonin or dopamine receptors did not stop psilocybin's effects in these mice. These results suggest that 5-HT2A receptor agonists can relieve depression through multiple pathways, independent of whether they cause hallucinations.

Study at a glance

Abstract

Major depressive disorder (MDD) is one of the most disabling psychiatric disorders in the world. First-line treatments such as selective serotonin reuptake inhibitors (SSRIs) still have many limitations, including a resistance to treatment in 30% of patients and a delayed clinical benefit that is observed only after several weeks of treatment. Increasing clinical evidence indicates that the acute administration of psychedelic agonists of the serotonin 5-HT2A receptor (5-HT2AR), such as psilocybin, to patients with MDD induce fast antidepressant effects, which persist up to five weeks after the treatment. However, the involvement of the 5-HT2AR in these antidepressant effects remains controversial. Furthermore, whether the hallucinogenic properties of 5-HT2AR agonists are mandatory to their antidepressant activity is still an open question. Here, we addressed these issues by investigating the effect of two psychedelics of different chemical families, DOI and psilocybin, and a non-hallucinogenic 5-HT2AR agonist, lisuride, in a chronic despair mouse model exhibiting a robust depressive-like phenotype. We show that a single injection of each drug to wild type mice induces anxiolytic- and antidepressant-like effects in the novelty-suppressed feeding, sucrose preference and forced swim tests, which last up to 15 days. DOI and lisuride administration did not produce antidepressant-like effects in 5-HT2A-/- mice, whereas psilocybin was still effective. Moreover, neither 5-HT1AR blockade nor dopamine D1 or D2 receptor blockade affected the antidepressant-like effects of psilocybin in 5-HT2A-/- mice. Collectively, these findings indicate that 5-HT2AR agonists can produce antidepressant-like effects independently of hallucinogenic properties through mechanisms involving or not involving the receptor.