Neuromedin U receptor 2 agonists suppress cocaine self-administration in male rats

Rationale Cocaine use disorder ( CUD ) remains without an FDA-approved pharmacotherapy, highlighting the need for novel mechanistically distinct targets. Prior work implicates neuromedin U ( NMU ) and its receptor NMU receptor 2 ( NMUR2 ) in cocaine-directed behavior, but NMUR2 peptide-based approaches have limited translational utility. Objectives Here, we tested whether the previously characterized NMUR2-active small molecules NY0116 and NY0128 reduce cocaine self-administration under a progressive ratio schedule in male rats. Because reduced progressive ratio responding can also reflect broader behavioral disruption, we examined response latency, inactive lever responding, and locomotor activity. Methods Rats were trained to self-administer intravenous cocaine (0.25 mg/kg/infusion) and tested after systemic administration of NY0116 or NY0128. Results Both compounds reduced cocaine-maintained responding at the highest dose tested, including reductions in breakpoint and active lever responding. Lever discrimination was not significantly altered at the effective dose, arguing against loss of task discrimination as the explanation for reduced cocaine intake. Individual-animal analyses showed no significant correlation between levels of locomotor activity and cocaine infusions during NY0128 test sessions, indicating that locomotor output did not account for individual differences in cocaine intake. Conclusions These findings demonstrate that NY0116 and NY0128 are effective in reducing cocaine self-administration in male rats, providing strong evidence that NMUR2 is a promising target for developing new CUD pharmacotherapies.