Methylone produces antidepressant-relevant actions and prosocial effects.

Methylone (3,4-methylenedioxy-N-methylcathinone) is a rapid-acting entactogen that has been shown to have significant benefits in patients with post-traumatic stress disorder and major depressive disorder and is well tolerated in phase 1 clinical trials. A recent preclinical study reported that methylone produced robust antidepressant-like actions in naïve rats. However, its antidepressant effects on various stress-related psychopathologies and other neuropsychological actions remain unclear. In the present study, we examined the antidepressant-relevant effects of methylone in learned helplessness (LH) and social defeat stress C57BL/6J male mouse models and further explored its sociability-relevant neuropsychological actions. Our results indicate that methylone produces antidepressant-relevant effects on the helpless phenotype, LH-evoked depressive-like behaviors, and psychosocial stress-induced social avoidance, and induced depressive-like behaviors. In addition, methylone was found to enhance social preference and increase various social behaviors, including social contact, sniffing, allogrooming, and following. Moreover, methylone appeared to elevate empathy-like phenotypes and was also found to increase helping-like behavior. Overall, the present results suggest that methylone plays an antidepressant-like role in various stress-relevant psychopathologies and could be an ideal antidepressant candidate. In addition, novel findings on the elevated tendencies of social preference and empathy-like and helping-like phenotypes reveal that methylone may have potential application in patients with social deficits.