Investigating the role of 5-HT2A and 5-HT2C receptor activation in the effects of psilocybin, DOI, and citalopram on marble burying in mice

Psychedelic drugs acting as 5-hydroxyptryptamine 2A receptor (5-HT_2AR) agonists have shown promise as viable treatments of psychiatric disorders, including obsessive-compulsive disorder. The marble burying test is a test of compulsive-like behavior in mice, and psychedelics acting as 5-HT_2AR agonists can reduce digging in this test. We assessed the 5-HT₂R contribution to the mechanisms of two 5-HT_2A agonists on digging behavior in female NMRI mice, using citalopram as a reference compound. While the 5-HT_2AR antagonist M100907 blocked the effect of DOI and the 5-HT_2CR antagonist SB242084 blocked the effect of citalopram, neither antagonist blocked the effect of psilocybin. This study confirms 5-HT_2AR agonism as a mechanism for reduced compulsive-like digging in the MB test and suggests that 5-HT_2A and 5-HT_2CRs can work in parallel on this type of behavior. Our results with psilocybin suggest that a 5-HT₂R-independent mechanism also contributes to the effect of psilocybin on repetitive digging behavior.