Disruption of emotional processing by GBR 12909 in male and female mice highlights novel behavioral paradigms relevant to bipolar disorders

Bipolar disorders (BD) are defined by a chronic recurrence of manic and depressive phases. Along with mood, acute phases are associated with altered emotions. The biological underpinnings of these changes are unresolved, mostly because modeling the cycling nature of BD is still a major challenge in preclinical studies. One model is based on GBR 12909 administration, a dopamine transporter inhibitor aiming at mimicking some dimensions of mania. It has recently been shown that this model generates a mixed phenotype with negative hedonic biases and anxiety along with hyperlocomotion. These studies have been only performed in male animals, and other behavioral dimensions relevant for BD remain to be explored, in particular recognition of conspecifics emotions and reactivity to danger. The objective of this study is to further characterize the GBR model in both sexes by introducing two novel behavioral assays, the sweeping/looming disk and the negative emotion recognition tasks to evaluate response to threat and emotion discrimination. First, we replicated the previous results in the GBR model: higher anxiety, hyperlocomotion, anhedonia in males. These phenotypes were less pronounced in females. GBR also induced a hypersensibility to threat in both sexes in the sweeping/looming disk. GBR abolished preference for the emotional target only in males, suggesting altered emotion recognition. This work introduces new phenotypic dimensions relevant to study BD and highlights the necessity to study both sexes which are not strictly equivalent in their behavioral responses.