Influência do sistema histaminérgico cerebelar na consolidação da memória emocional de camundongos

Abstract

This study investigated the function of cerebellar histaminergic system on emotional memory consolidation. The cerebellar vermis of male mice were implanted with guide cannulae, and after three days of recovery, the animals were submitted to the elevated plus maze (EPM) or the inhibitory avoidance test (IA) on two consecutive days. Immediately after the first day, animals received a microinjection of histaminergic drugs into the cerebellar vermis: experiment 1, animals received microinjections of saline (SAL) or histamine (HA) (0.54, 1.36, 2.72, and 4.07 nmol/0.1 microliter); experiment 2, animals received a microinjection of SAL or the H1 antagonist chlorpheniramine (CPA, 0.016, 0.052 or 0.16 nmol/0.1 μl); experiment 3, SAL or the H2 antagonist ranitidine (RA, 0.57, 2.85 or 5.7 nmol/0.1 μl); experiment 4, SAL or HA 5 minutes after a pretreatment with 0.16 nmol CPA or SAL; and experiment 5, SAL or HA 5 minutes after a pretreatment with 2.85 nmol ranitidine (RA) or SAL. In the EPM, the decrease of open arm exploration (% entries and % time spent in the open arms) in Trial 2 relative to Trial 1 was used as a measure of learning and memory; while in the IA, latency to cross to the dark compartment was used to evaluate memory retention. Data were analyzed using ANOVA and Duncan‟s test. The results of experiment 1 showed that animals microinjected SAL and 0.54 and 1.36 nmol HA reduced percentage of open arm entries and time, while mice microinjected with HA 2.72 and 4.07 nmol did not decrease open arm exploration on trial 2; which indicates that histamine induced a dose-dependent inhibitory effect on memory consolidation. In the IA task, results showed that 1.36 nmol histamine facilitated memory consolidation, suggesting a different action of HA in a memory model that uses punishment. In the experiment 2, microinjections with CPA did not present behavioral effects in the EPM or in the IA at the doses used (0.016, 0.052 and 0.16 nmol). The results of experiment 3 showed that 5.7 nmol RA impaired memory consolidation on both protocols. The experiment 4 demonstrated that animals treated with HA did not reduce the avoidance to the open arms on retesting, and indicated that CPA did not altered behavioral parameters by itself, but the pretreatment with CPA reverted histamine-induced impairment on memory consolidation, which suggests that histamine effect on the EPM was mediated by H1 receptors. In the IA test, the results showed that the groups that received CPA+HA and SAL+HA showed a significant difference in latency on the second day of testing in relation to group SAL+SAL , while the group treated with CPA + SAL showed no difference with the control group. These results show that microinjection of histamine in the cerebellar vermis increased latency time and that pretreatment with CPA did not reverse this effect. For the fifth experiment, the results showed that animals microinjected with SAL+SAL and RA+SAL reduced the percentage of entries and time spent in open arms in the EPM while the groups treated with RA+HA and SAL+HA showed no difference between test days. These results show that RA did not alter memory consolidation and was unable to reverse the effect of histamine. In the IA, there was significant difference between SAL+SAL and SAL+HA groups, showing the facilitatory effect of histamine on memory consolidation of IA. The groups that received combined injection of RA+SAL and RA+HA showed no significant difference compared to control, which shows that the RA had no effect by itself, but when applied before histamine was able to reverse its effect. Our results suggest different histamine effects in tasks involving anxiety or fear.