PRECLINICAL EFFORT BASED DECISION-MAKING FRAMEWORK FOR RATS: EVALUATION OF ANHEDONIA AND MOTIVATIONAL IMPAIRMENTS ACROSS PSYCHIATRIC CONDITIONS

Negative symptoms, including anhedonia and diminished motivation, are frequently seen in depression and schizophrenia. Given the limited predictive value of preclinical rodent behavioural assays, a modified version of the rat Effort Expenditure for Reward Task (EEfRT), a translational paradigm, was developed and validated. The EEfRT assesses motivation and effort-based decision-making by having subjects choose between a high-effort/high-reward (HEHR) option and a low-effort/low-reward (LELR) alternative enabling quantification of motivational states and evaluation of pharmacological manipulations. First, to validate the EEfRT, we clustered rats into two groups based on their baseline performance: high preference (HP) and low preference (LP). In the HP group, pharmacological anhedonia was successfully induced with dopamine-depleting agent tetrabenazine and subsequently reversed with dopamine reuptake-inhibitor bupropion. In the LP group, natural anhedonia was reversed with bupropion alone. Cross‑validation analyses showed no correlation between EEfRT performance and anxiety measures or food preference, suggesting that the EEfRT paradigm selectively captures motivational dimensions of behaviour. Lastly, in a drug-repurposing experiment, we investigated the impact of various GLP-1 agonists on EEfRT performance. All GLP-1 receptor agonists consistently reduced food intake, confirming their expected appetite-suppressing effects. Exenatide decreased the effort animals exerted for food rewards, while liraglutide and semaglutide did not alter effort expenditure, indicating distinct effects among GLP-1 agonists on motivation. Findings highlight that GLP-1 agonists differ in their impact on reward-related behaviours, beyond appetite suppression. Our further aim is to characterize how depression- and schizophrenia-related neurobiological disturbances produce overlapping or distinct patterns of motivational dysfunction by using different disease models.