A participação dos receptores histaminérgicos H4 na modulação da memória emocional e no controle motor em camundongos

Abstract

Experimental evidence suggests the participation of the cerebellum in motor and non-motor functions. Since recent results demonstrate the participation of the histaminergic cerebellar system in the consolidation of memory, this study investigated the effect and the understanding of the molecular bases of the histaminergic H4 agonist (VUF-8430) microinjection in the consolidation of emotional memory in mice submitted to the elevated plus maze (EPM) and the inhibitory avoidance task (IAT) as well as in motor control in mice submitted to the rotarod test. On the fourth day after surgical recovery from the procedure to implant a cannula, the animals received saline (SAL) or VUF (0.15 nmol; 0.49 nmol; e 1.48 nmol/0.1 μl) administered post-exposure. Experiments 1, 2 and 3 were performed on two consecutive days: Exposure and 24h after, the re-exposure. Experiment 1: was held in the EPM and immediately post-T1, the pharmacologic treatment occurred; in T2, there were only re-exposure to EPM. The decrease in activity in the open arms (OAE and OAT) between T1 and T2, inferred the emotional memory. Experiment 2: was held in the IAT and the pharmacological treatment was post-D1; in D2, the animals were only re-exposed to the IAT. The increase or decrease of latencies in D2 compared to D1 inferred the emotional memory. Experiment 3: was held in the rotarod and the animals received the drug treatment post-R1; in R2, the animals were only re-exposed, featuring motor learning. The increase or decrease in R2 latencies compared to R1, inferred the motor learning. Experiment 4: VUF-8430 was I.P. injected at a dose of 500 ng/kg to investigate protein expression by phosphorylation of the CREB transcription factor, using the Western blotting technique, in the cerebellar vermis and in classic structures linked to emotional memory (prefrontal cortex, amygdala and hippocampus). Results: in Experiment 1, VUF (0.49 nmol and 1.48 nmol) impaired the consolidation of emotional memory in the EPM; in Experiment 2, VUF (1.48 nmol) impaired the consolidation of emotional memory in the IAT; in Experiment 3, VUF (0.49 nmol and 1.48 nmol) impaired the consolidation of motor learning in the rotarod; in Experiment 4, there was a decrease in protein expression (CREB and pCREB) in the cerebellar vermis and prefrontal cortex in mice. Conclusions: the highest dose of VUF-8430 (1.48 nmol), microinjected in the cerebellar vermis in mice, induced deficit in learning and memory consolidation in the models used in the present study (EPM, IAT and rotarod). In addition, the decrease in the protein expression in the cerebellar vermis verified by CREB and pCREB levels when injected I.P. the highest dose of the H4 receptor agonist (VUF-8430) can corroborate these deficits.