Sex-dependent disruption of affective behaviors by GBR 12909: relevance 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 pharmacological model is based on GBR 12909 administration, a dopamine transporter inhibitor aiming at mimicking some dimensions of mania. Recent findings indicate that this model generates a mixed phenotype, combining hyperlocomotion with negative hedonic biases and anxiety. These studies have only been performed in male animals, and other behavioral dimensions relevant for BD remain to be explored, in particular recognition of conspecific emotional states and reactivity to danger. The objective of this study is to further characterize the GBR model in mice of 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 and did not reach significance in females. GBR also induced a hypersensitivity 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.