Interação dos sistemas histaminérgico e dopaminérgico cerebelar na modulação de funções motoras e não motoras em camundongos

Abstract

The interaction between neurotransmitters triggers several possibilities for synaptic integration. Evidence suggests that the cerebellum is involved in processing both motor and non-motor functions. However, the interaction between the cerebellar histaminergic and dopaminergic systems in the modulation of these functions is unclear. This study aimed to investigate the role of the cerebellar dopaminergic system in motor behavior and motor learning, and in the acquisition of aversive emotional memory in mice, as well as to investigate the interaction of the cerebellar histaminergic and dopaminergic systems in the same functions. For this, the animals received the implantation of a guide cannula into the cerebellar vermis through stereotaxic surgery. After recovery they underwent the drug microinjection procedure, with an administration of 0.1µl of the drug, depending on the experimental group in which they were allocated. To evaluate the motor performance and motor learning of the mice, the time spent on the Rota-rod and the crossing latency on the balance beam were measured in five steps (habituation, microinjection, stage 1, stage 2, stage 3). To assess the acquisition of emotional memory, the mice underwent the inhibitory avoidance test, and the time to cross from the light side to the dark side was measured at all exposures. After the end of the experiments, the animals received a deep dose of anesthesia, underwent cardiac perfusion with 4% paraformaldehyde fixative in phosphate buffered saline (PBS), and their brains were stored. Statistical analysis of behavioral data was performed by repeated measures analysis of variance. Tukey's post hoc test was used in case of significant differences in the analysis of variance. Intravermis cerebellar administration alone of Dopamine and SCH 23390 (D1 dopamine antagonist) had no effects on motor behavior, motor learning and emotional memory in this study. The microinjection of Eticlopride (D2 dopamine antagonist) had no effect on motor behavior and motor learning, but the highest dose improved the acquisition of emotional memory in the inhibitory avoidance task (p=0.01). The combined injection of Histamine and SCH23390 had no effect on emotional memory acquisition in inhibitory avoidance. However, animals that received this drug combination showed a significant decrease in performance and motor learning in rotarod (p=0.02), and a tendency to increase the balance beam crossing time (p=0.07). The combined injection of Histamine and Eticlopride had no effect on motor learning, but it improved the emotional memory acquisition in the inhibitory avoidance test in mice in this study (p=0.07). In this study, we identified that Histamine administration was able to potentiate the action of sub-effective doses of D1 and D2 dopaminergic antagonists in different experimental models, which strengthens the hypothesis of interaction of these systems in the processing of motor and non-motor functions. D1 receptors seem to be predominantly related to motor learning processes, while D2 receptors seem to be predominantly related to the processing of aversive memories.