EMPATHOGENIC SUBSTANCES HAVE DISTINCT EFFECTS ON DIFFERENT SOCIAL BEHAVIORAL DOMAINS

Social dysfunction is a core feature of various psychiatric disorders affecting millions worldwide. Given the fundamental role of social behavior in mental health, there is growing interest in pharmacological interventions targeting social deficits. In this study, we used 3,4-methylenedioxymethamphetamine (MDMA), a well-known prosocial substance, and d-fenfluramine, a clinically approved serotonin-releasing drug. These compounds reverse the direction of monoamine transporters, leading to increased neurotransmitter release. Here, we tested MDMA and d-fenfluramine in a battery of socio-cognitive tasks in mice. We observed substance-specific effects on different domains of social behavior and interaction dynamics. MDMA increased social interaction in a social vs. non-social choice task, without affecting free social interaction or social memory. In contrast, d-fenfluramine influenced free social interaction and social memory, but not social vs. non-social discrimination. Importantly, both compounds altered emotion discrimination, effect replicated by the specific optogenetic stimulation of serotonin terminals in the mPFC, suggesting a key role of serotonin in these behavioral modifications. Our findings suggest that different empathogens have distinct effects on social behavior, possibly due to domain-specific contributions of various monoamines. These data start to provide novel perspectives for developing targeted therapies for specific social abnormalities present in psychiatric disorders.