MSc (Pharmacology), North-West University, Potchefstroom Campus Obsessive-compulsive disorder (OCD)1 is a chronic and debilitating neuropsychiatric condition affecting 1 – 3% of the world population. The condition is characterized by two main symptom cohorts namely recurrent, distressing and intrusive thoughts (obsessions) and seemingly purposeless rigid and repetitive behaviors (compulsions). Furthermore, OCD patients present with notable cognitive rigidity and behavioral inflexibility. This is characterized by deficits in reward and punishment feedback processing which are regulated by dopaminergic and serotonergic neurotransmission. In addition, OCD causes remarkable distress and severely impairs almost every aspect of an individual’s life. Although chronic high-dose selective serotonin reuptake inhibitor (SSRI)2 intervention is regarded as the first-line pharmacological treatment for OCD, 40 – 60% of patients remain symptomatic and full remission is usually not achieved. Over the preceding decades, rodent models of OCD have helped us to further our understanding of the disorder and its treatment. However, these are characterized by noteworthy limitations for example, they are exceptionally time-consuming and expensive and have a low-throughput capacity. In this regard, zebrafish (Danio rerio) have emerged as an alternative framework for the pre-clinical study of neurobehavioral disorders. The most important advantages of applying zebrafish include 1) their broad homology to rodent and human neurobiology, presenting with almost fully conserved dopaminergic and serotonergic systems, 2) their highly social nature which enables them to shoal and seek out conspecifics (same species fish), 3) their ability to clearly distinguish between colors, which facilitates color-dependent learning, and 4) their sophisticated sensory, motor and motivational systems that are well-suited for experiments into associative learning. As such, the present investigation was conceptualized to provide a foundation for establishing a novel, high-throughput screening test for anti-compulsive drug action using zebrafish as a model organism by exploiting their natural reward-seeking behavior such as elevated motivational drive to engage in social interaction in a cue-reward contingency learning paradigm. Considering the current theories describing the roles of dopamine and serotonin in OCD, we aimed to induce compulsive-like persistence with the dopaminergic agonist, apomorphine, and further investigated if such persistence, if present, would be reversed by chronic escitalopram, an SSRI. Seven groups of zebrafish (n = 6 per group) were exposed for 24 days (1 hour per day) to either control (normal tank water), apomorphine (50 or 100 𝜇g/L), escitalopram (500 or 1000 𝜇g/L) or a combination 1 obsessive-compulsive disorder 2 selective serotonin reuptake inhibitor (A100/E500 or A100/E1000 𝜇g/L). Cue-reward learning was assessed over three phases i.e. Phase 1 (contingency learning), Phase 2 (dissociative testing), and Phase 3 (re-associative testing). We demonstrate that 1) sight of social conspecifics is an inadequate reinforcer of contingency learning under circumstances of motivational conflict, 2) dopaminergic and serotonergic intervention lessens the importance of an aversive stimulus, increasing the motivational valence of social reward, 3) while serotonergic intervention maintains reward-directed behavior, high-dose dopaminergic intervention bolsters cue-directed responses and 4) high-dose escitalopram reverses apomorphine-induced behavioral inflexibility. The results reported here are supportive of current dopamine-serotonin opponency theories and confirm that zebrafish may be a potentially useful species in which to emulate compulsive-like behaviors. Although compulsive-like persistence toward habitual, cue-directed behavior was not induced by either dose of apomorphine, fish exposed to high-dose apomorphine present with behavior more akin to behavioral inflexibility compared to their counterparts in all other exposure groups. This was reversed by chronic high, but not lower dose escitalopram, a finding that is supportive of current dopamine-serotonin opponency theory. The apparent aversion demonstrated by drug-naive subjects to the color red was unexpected and has complicated the interpretation of our results. Indeed, it is likely that the use of a more-preferred color in this population may have yielded a more robust result, a possibility that we will investigate in future. In conclusion, typical theories of neurotransmitter involvement in OCD1 for example imbalanced crosstalk between dopamine and serotonin amongst others, provides a useful background for investigating compulsive-like behaviors in animals. Not only do the findings presented here confirm the viability of zebrafish as a model species in which to study the neurobiological and cognitive processes underlying dopamine-serotonin interactions under circumstances of motivational conflict, it also provides valuable direction for future endeavors toward the development of a novel screening framework that is sensitive for anti-compulsive drug action. Masters