¹Transpharmation, Neuroscience, Fergus, Canada, ²University of Cambridge, Psychology, Cambridge, United Kingdom

Background: Obsessive–compulsive disorder (OCD) is characterized by maladaptive repetitive behaviors and impaired inhibitory control, processes strongly regulated by monoaminergic neurotransmission.

Aims & Objectives: In this study, we evaluated three clinically relevant compounds with distinct pharmacological profiles: citalopram (selective 5-HT reuptake inhibitor; SSRI), atomoxetine (selective NA reuptake inhibitor; SNRI), and Bupropion (mixed DA/NA reuptake inhibitor; SNRI/SDRI), using two complementary rodent paradigms, Schedule-Induced Polydipsia (SIP) and 5-Choice Serial Reaction Time Task (5-CSRTT) on compulsive behaviors.

Method: Thirty Wistar rats were used in the SIP paradigm and sixty Long–Evans rats were used in the 5 CSRTT. These large group sizes enabled drug effect on performance to be evaluated in extreme compulsive endophenotypes as well as overall cohort. Rats were trained in their respective tasks until stable baseline performance was achieved. For the SIP cohort, stability was defined by consistent levels of water consumption, while for the 5-CSRTT cohort, stable performance was defined under standard task parameters (0.75 s stimulus duration, 5 s inter-trial interval, and 100 trials). Once these criteria were met, animals were tested with different doses of the compounds. SIP testing was conducted under the same schedule, whereas 5-CSRTT testing was performed using the long inter-trial interval version of the task to increase sensitivity to compulsive and impulsive-like responding.

Results: Our findings demonstrate a clear dissociation between monoaminergic systems across these two assays. Citalopram consistently reduced compulsive-like behavior in both SIP and 5-CSRTT, supporting the central role of serotonergic signaling in suppressing repetitive and inflexible responding and aligning with its clinical efficacy in OCD. This effect was particularly evident in the extreme high-compulsive subgroup. Atomoxetine showed a task-dependent profile, with minimal effect on compulsive-like behavior measured in SIP, while robustly decreasing it in the 5-CSRTT.In contrast, Bupropion increased compulsive behavior in both paradigms, consistent with DAergic enhancement may exacerbate repetitive responding and behavioral disinhibition.

Discussion & Conclusions: Together, these findings confirm SIP and 5-CSRTT as complementary translational models for OCD and demonstrate that compulsive behavior is multidimensional, with distinct aspects captured by these two behavioral assays. They also emphasize the importance of a multi-assay approach to reliably differentiate reliable anti-compulsive effects from nonspecific changes in motivation, arousal, or activity.