Reinforcement sensitivity phenotype modulates the impact of chronic stress on hedonic capacity in rats, but not the response to fluoxetine

INTRODUCTION: Depression is a heterogeneous psychiatric disorder shaped by the interaction between environmental stress and individual traits, such as reinforcement sensitivity. These traits influence how individuals process rewarding and aversive outcomes, and affect both vulnerability to depression, and treatment response. Here, we investigated whether reinforcement sensitivity-based phenotypes modulate behavioral outcomes of chronic stress and fluoxetine treatment in rats. METHODS: Using the probabilistic reversal learning task, 160 rats were classified into four phenotypes: dysthymic, irritable, pro-depressive, and pro-manic. Animals were then exposed to chronic restraint stress and treated with fluoxetine (10 mg/kg, i.p.) or vehicle, followed by behavioral screening in sucrose preference, progressive ratio schedule of reinforcement, and light-dark box tests. Computational reinforcement learning models were also fitted to probabilistic reversal learning performance to estimate learning rates and choice strategies. RESULTS: Results revealed phenotype-dependent effects of stress, with the pro-depressive group showing selective vulnerability to stress-induced anhedonia. Across phenotypes, chronic stress reduced sucrose preference and appetitive motivation, confirming its broad negative impact. Mathematical modeling paralleled these findings: pro-depressive rats had increased learning rates from negative outcomes, and were less likely to select choices with higher perceived value. Fluoxetine did not alleviate deficits; instead, it consistently decreased hedonic status and motivation while increasing anxiety-like behaviors, independent of phenotype or stress exposure. Consistent with this, fluoxetine further lowered learning rates, providing a mechanistic account of its paradoxical effects on reward learning. CONCLUSIONS: Our findings underscore the need for trait-informed approaches to antidepressant research and highlight potential adverse effects of fluoxetine on emotional and motivational processing.