Behavioral and pharmacological validation of the differential reinforcement of low-rate behavior paradigm in...

Depression remains a leading cause of disability worldwide, yet the predictive validity of many preclinical behavioral assays for antidepressant efficacy remains limited. The differential reinforcement of low-rate behavior (DRL) task has classically been used in rodents to identify antidepressant-like effects, but its utility in non-human primates (NHPs) has not been established. Here, we adapted the DRL task for use in adult male cynomolgus macaques ( Macaca fascicularis ) and evaluated its pharmacological sensitivity and translational relevance across 19 compounds spanning multiple drug classes. Antidepressants, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, noradrenergic reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, and phosphodiesterase-4 (PDE4) inhibitors, generally shifted DRL performance in an antidepressant-like direction, increasing reinforcers earned and inter-response times while decreasing response output. In contrast, benzodiazepine and antipsychotic control compounds did not produce a consistent antidepressant-like profile, whereas stimulant effects were mixed, with nicotine and cocaine also producing overlapping antidepressant-like behavioral effects. Importantly, the primate DRL task identified antidepressant-like effects of PDE4 inhibitors while also capturing emesis, a dose-limiting side effect not observable in rodent models. These findings support the primate DRL task as a translationally relevant platform for screening antidepressant-like efficacy, while also highlighting important design considerations for interpreting pharmacological sensitivity in the NHP setting. By modeling behavioral processes implicated in depression, including response inhibition and temporal regulation, this assay offers a unique opportunity to bridge preclinical and clinical antidepressant development with improved sensitivity to both efficacy and tolerability.