The neural histaminergic system modulates cognitive performance in various animal models. However, little is known about the effects of the H4 histaminergic receptor in the central nervous system. The purpose of this study was to investigate the effect of histaminergic H4 agonist VUF-8430 microinjection into the cerebellar vermis on the consolidation of emotional memory in mice subjected to the elevated plus maze (EPM) and inhibitory avoidance task (IAT). All experiments were performed on two consecutive days: exposure (T1 and D1) and 24h after, which we called re-exposure (T2 and D2). The animals received saline (SAL) or VUF (0.15 nmol; 0.49 nmol; 1.48 nmol/0.1μl) administered post-exposure. Experiment 1 was conducted in the EPM, and the animals were free to explore the maze for 5min. In T1, immediately after exposure, the pharmacological treatment was given; in T2, there was only re-exposure to the EPM. Experiment 2 involved the IAT, and the pharmacological treatment was provided post-D1; in D2, the animals were only re-exposed to the IAT. In Experiment 1, increased open arm exploration (% open arm entries and% open arms time) for 0.49 and 1.48nmol of VUF were recorded in T2 compared to T1. In Experiment 2, a significant decrease in consolidation latency was recorded for the group that received 1.48nmol of VUF compared to the SAL group in D2. These results indicate that a 1.48nmol VUF microinjection into the cerebellar vermis impaired performance in both models, even though one model was anxiety-mediated (EPM) and the other was fear-mediated (IAT).

The neural histaminergic system innervates the cerebellum, with a high density of fibers in the vermis and flocculus. The cerebellum participates in motor functions, but the role of the histaminergic system in this function is unclear. In the present study, we investigated the effects of intracerebellar histamine injections and H1, H2 and H3 receptor antagonist injections (chlorpheniramine, ranitidine, and thioperamide, respectively) and H4 receptor agonist (VUF-8430) on locomotor and exploratory behaviors in mice. The cerebellar vermis of male mice was implanted with guide cannula. After three days of recovery,the animals received microinjections of saline or histamine (experiment1), saline or chlorpheniramine (experiment 2), saline or ranitidine(experiment 3), saline or thioperamide (experiment 4), and saline or VUF-8430 (experiment 5) in different concentrations. Five minutes postinjection,the open field test was performed. The data were analyzed using one-way ANOVA and Duncan's post hoc test. The microinjections of histamine, ranitidine or thioperamide did not lead any behavioral effects at the used doses. In contrast, animals that received chlorpheniramine at the highest dose (0.16 nmol) and VUF-8430 at the highest dose (1.48 nmol)were more active in the open field apparatus, with an increase in the number of crossed quadrants, number of rearings and time spent in the central area of the arena, suggesting that chlorpheniramine and VUF-8430 modulates locomotor and exploratory behaviors in mice.

Studies have shown that an injection with the histamine H4 receptor agonist VUF-8430 modulates emotional memory processes. In the present study, the aim was to verify if intraperitoneal ( ip ) injection of VUF-8430 (500 ng/kg) in mice affects the synthesis of proteins required for memory consolidation processes by activating the phosphorylation of CREB (pCREB) in classical structures linked to emotional memory (prefrontal cortex, amygdala, and hippocampus) and the cerebellar vermis, a structure that has also been recently implicated in emotional memory. The results obtained using western blot analysis demonstrated that VUF-8430 induced a decrease in CREB and pCREB levels in the cerebellar vermis and prefrontal cortex, suggesting that this dose impaired the activation of cell signaling pathways in these structures. There was no change in protein expression in the amygdala and hippocampus. Our results are preliminary, and further investigations are needed to investigate the role of the H4 receptors in the central nervous system.

H1 receptor histaminergic antagonist, chlorpheniramine (CPA) participates in cognitive performance in various animal models. However, little is known regarding the effects of CPA microinjection into the amygdala on emotional behavior. The purpose of this study was to investigate whether CPA microinjection into the amygdala has the same effect on two models, one anxiety- and the other fear-mediated, in various memory stages using the elevated plus maze (EPM) and the inhibitory avoidance task (IAT) tests. Two experiments were performed with seventy-two adult male Swiss mice. Behavioral testing was performed on two consecutive days, and in both experiments, before each trial, the animals received bilateral microinjections of saline (SAL) or CPA (0.16 nmol). The animals were re-exposed to the EPM or IAT 24h after the first trial. Four experimental groups were tested: SAL-SAL, SAL-CPA, CPA-SAL and CPA-CPA. In experiment 1, a decreased open arm exploration (% open arm entries, %OAE and% open arms time, %OAT) for SAL-SAL and SAL-CPA was showed, while these measures did not decrease for the CPA-SAL and CPA-CPA groups in Trial 2. In experiment 2, an increase of retention latency in relation to training 2 for the groups SAL-SAL and CPA-SAL and a significant decrease in latency for the group SAL-CPA was revealed. These results indicate that chlorpheniramine microinjection into the amygdala impairs emotional memory acquisition and/or consolidation in the EPM and retrieval of IAT.

This study investigated the effects of bilateral intraamygdalar microinjections of PNU-282987, a nicotinic cholinergic agonist, on anxiety and the reversal of amnesia induced by chlorpheniramine (CPA), an H1 histaminergic antagonist, in mice subjected to the elevated plusmaze (EPM). Two experiments were performed with seventy-nine adult male Swiss mice. The isolated microinjections of PNU-282987 did not produce effects on emotional memory; however, the combined microinjections of PNU-282987 and CPA were able to reverse the deficit in memory induced by CPA (ANOVA, p<0.05). Taken together, these results suggest that intraamygdalar injections of PNU-282987 did not induce effects on anxiety and emotional memory per se; however, concurrent microinjections of PNU-282987 and CPA-reverse amnesia induced-CPA which is suggestive of an interaction between the histaminergic and cholinergic systems in the modulation of emotion memory acquisition in mice.