Epilepsias e neurotransmissão dopaminérgica: expressão de receptores, efeito de moduladores e avaliação do comportamento animal no modelo Wistar Audiogenic Rats (WAR

Abstract

Epilepsies are diseases of the Central Nervous System characterized by irregular and recurrent electrical discharges and, frequently, epileptic patients are also affected by neuropsychiatric comorbidities, such as depression and anxiety. Both epilepsy and comorbidities may be related to changes in dopaminergic neurotransmission. In the present work, we investigated the expression of D1- and D2-type receptors in Wistar and WAR (Wistar Audiogenic Rats) animals, an experimental model of epilepsy. Furthermore, we investigated the effects of agonists with high specificity to these receptors on animal behavior. Male WAR and Wistar rats were used, and the WAR were divided according to the behavioral severity index (BSI, IGC in portuguese) observed after the audiogenic stimulus. The groups used were: Wistar control group (Saline, 0.9% saline solution), WAR control (Saline, 0.9% saline solution), Wistar treated with D1 agonist (SKF-38393, 40 pmol/µL), WAR treated with D1 agonist (SKF-38393, 40 pmol/µL), Wistar treated with D2 agonist (quimpirole, 40 pmol/µL) and WAR (quinpirole, 40 pmol/µL). The solutions were administered intra-amygdalarly with an interval of two days between administrations. Biochemical analyzes of western blot, immunofluorescence and immunohistochemistry were performed to evaluate the expression of dopamine receptors type 1 (RD1) and 2 (RD2) in slices of hippocampus, prefrontal cortex, amygdala and striatum of Wistar and WAR. For the hippocampus, we observed an increase in the expression of RD1 in WAR animals when compared to Wistar animals (western blot) and a decrease in the expression of the enzyme tyrosine hydroxylase and presynaptic RD2 for the CA1 region (immunofluorescence). We also observed an increase in RD1 expression for the infralimbic region of the prefrontal cortex in WAR animals when compared to Wistar animals. In addition, a decrease in the expression of the enzyme tyrosine hydroxylase and total RD2 was observed for the region of the basolateral amygdala (immunofluorescence) in WAR animals when compared to Wistar animals. Subsequently, the behavioral analysis was performed, followed by the administration of the agonists. In the elevated plus maze test, we observed greater entry into open trimmed arms for WAR animals treated with quinpirole when compared to control WAR animals. Finally, we evaluated the IGC observed in WAR animals after the administration of the same agonists. The decrease in this index in WAR animals treated with quinpirole when compared to control WAR animals was also confirmed. In summary, and for the first time in the literature as far as we know, our treatments, especially with D2 receptor agonist, were able to change behavioral aspects in WAR when compared to control groups, suggesting the modulation of the dopaminergic system and related behavioral manifestations. These results reinforce the interest in increasing knowledge related to modulators of the dopaminergic system in epilepsy, as potential drug candidates for the treatment of neuropsychiatric comorbidities in epileptic patients.