GBR 12909, a Selective Dopamine Transporter Inhibitor, Differentially Modulates Affective, Exploratory and Cognitive Domains in Zebrafish

ABSTRACT

Dopamine plays an important role in several biological functions, such as reward, movement regulation and cognition. Physiological alterations in dopamine transporter (DAT) are related to psychiatric conditions, including bipolar disorder (BD), a condition characterized by intense shifts in mood, behaviour and energy, alternating between manic and depressive states. Administration of GBR 12909, a selective dopamine reuptake inhibitor, has been considered a suitable model to assess BD‐related phenotypes, yet the integration of anxiety‐like, despair‐like, cognitive and spatiotemporal behavioural dimensions has not been systematically evaluated. Here, we evaluated the acute behavioural effects of GBR 12909 using a multidomain behavioural assessment in adult zebrafish. Fish received a single intraperitoneal administration of GBR 12909 (15 mg/kg) and 30 min after, were challenged to the open field test (OFT), light–dark test (LDT), shallow water test (SWT) and Free Movement Pattern Y‐Maze (FMP Y‐Maze). GBR 12909‐treated zebrafish exhibited increased time in homebase during OFT, prominent scototaxis and hyperactivity in LDT, increased immobility and hypolocomotion in SWT, along impaired cognitive flexibility and stereotypical behaviours in the FMP Y‐maze. These data reflect affective and cognitive disturbances consistent with dopaminergic overstimulation that triggers manic‐ and depressive‐like phenotypes, thereby recapitulating behavioural phenotypes relevant to multiple domains affected in BD. Collectively, our findings support that GBR12909 elicits dopaminergic‐driven behavioural phenotypes relevant to multiple domains of BD, providing a translational model for studying the neurobiological bases of DAT inhibition across distinct behavioural domains.