ANTIDEPRESSANT-LIKE EFFECTS OF PSYCHEDELICS IN A CHRONIC DESPAIR MOUSE MODEL: IS THE 5-HT_2A RECEPTOR THE UNIQUE PLAYER?

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. A recent paradigm shift in the treatment of MDD was the discovery that psychedelic agonists of the serotonin 5-HT_2A receptor (5-HT_2AR), such as psilocybin induce rapid and lasting antidepressant effects even in patients resistant to conventional antidepressants. However, the involvement of the 5-HT_2AR in these antidepressant effects remains controversial. Furthermore, whether the hallucinogenic properties of 5-HT_2AR agonists are mandatory to their antidepressant activity is still an open question.

The study led by Dr Carine Bécamel (Team “Neuroproteomics and signaling of brain disorders” headed by Philippe Marin) addressed these issues by investigating 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. Using different behavioral tests to assess the anxiety-depressive state of the animals, the study showed that these 3 drugs induce immediate and lasting antidepressant effects. However, unlike DOI and lisuride, the antidepressant effects of psilocybin, a drug currently used in numerous clinical trials, are independent of 5-HT_2AR activation.

Collectively, these findings indicate that 5-HT_2AR agonists can produce antidepressant-like effects independently of hallucinogenic properties through mechanisms involving or not involving the receptor.

Read the publication