Modelos experimentais de transtorno afetivo bipolar em peixe-zebra: ênfase nos efeitos neurocomportamentais da inibição do transportador de dopamina pelo GBR 12909

Abstract

Bipolar disorder (BD) is a condition that affects 1-2% of the population worldwide. This condition is characterized by recurrent and extreme mood swings, including mania/hypomania and depression episodes. The pathophysiology of BD is complex and may involve changes in oxidative parameters and dopaminergic system functionality. Although rodents are widely used in translational research, alternative experimental models may aid the assessment of evolutionarily conserved mechanisms underlying of BD and its related behavioral phenotypes. The zebrafish (Danio rerio) have been considered a suitable vertebrate system in translational neuropsychiatric research, due to genetic tractability, physiological conservation, and well-characterized behavioral responses. This thesis aims to validate the use of adult zebrafish as a model organism for studies of neurobehavioral changes related to BD. In the first study, we conducted a literature review corroborating the use of zebrafish as a promising tool to investigate the neurobiological bases associated with behaviors paralleling those found in BD, discussing the advantages and limitations of this aquatic species to validate novel experimental models. The presence of conserved cellular mechanisms, as well as the wide range of behaviors correlated with BD measured by different behavioral paradigms, are important factors in aiding the discovery of novel pharmacological therapies. In the second study, we investigated whether a dopamine transporter inhibitor, GBR 12909, is capable to mimic phenotypes similar to BD in adult zebrafish. An acute treatment was performed consisting of a single intraperitoneal injection of GBR 12909 at different doses (3.75, 7.5, 15, and 30 mg/kg). To observe the temporal effects of GBR 12909 on the fish swimming pattern, locomotor and exploratory parameters were measured immediately after the administration period for 30 minutes. Locomotion, anxiety-like behavior, sociability, aggressiveness, depressive-like behavior, and parameters related to oxidative stress were measured 30 minutes after administration. GBR 12909 causes hyperactivity and anxiety-like behavior within the 30-minute period. After 30 minutes, GBR 12909 induced hyperlocomotion, anxiety-like behavior, decreased social preference and aggressiveness, as well as depressive-like behavior. Additionally, depending on the dose, GBR 12909 decreased SOD activity and TBARS levels, as well as increased GR activity and NPSH content. In summary, our data show that the use of zebrafish is an emerging tool to explore responses associated with BD in translational neuroscience research. Furthermore, dopamine transporter inhibition is capable of evoking neurobehavioral changes that recapitulate manic and depressive-like states observed in rodents, which may foster the discovery of novel neuroprotective strategies.