Intra-vermis H4 receptor agonist impairs performance in anxiety- and fear-mediated models

Abstract

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).

Systemic injection of an H4 receptor agonist induces a decrease in CREB and pCREB levels in the cerebellar vermis and prefrontal cortex in mice

“…On the other hand, a study by Galeotti et al (6) showed that VUF-8430 microinjected icv in mice reversed deficits in emotional memory induced by scopolamine in the IAT, but the microinjection alone did not show effects on emotional memory. In the present study, we showed that the acute administration of VUF-8430 induced a significant repression of CREB signaling expression in the cerebellar vermis that is associated with cognitive impairment, which could be related to the biochemical events associated with cognitive impairment found in our previous study (7).…”

“…Sanna et al (8) suggested that the H4 receptor subtype did not play a prominent role in the histaminergic modulation of memory processes; however, a recent study performed in our laboratory (7) showed that intravermis microinjections of VUF-8430 induced a deficit in memory consolidation in mice subjected to the EPM and IAT tests. On the other hand, a study by Galeotti et al (6) showed that VUF-8430 microinjected icv in mice reversed deficits in emotional memory induced by scopolamine in the IAT, but the microinjection alone did not show effects on emotional memory.…”

“…VUF-8430 (Sigma Chemical Co., USA), an H4 receptor agonist, was dissolved in sterile 0.9% saline solution and was administered via intraperitoneal ( ip ) injection at a dose of 500 ng/kg, adapted from previous studies conducted in our laboratory (7) and by Lim et al (5).…”

“…A study conducted by Galeotti et al (6) demonstrated that intracerebroventricular ( icv ) microinjections of this H4 receptor agonist reversed emotional memory deficits induced by scopolamine in mice subjected to an inhibitory avoidance task (IAT), which is a model related to fear expression. A recent study conducted by Fernandes et al (7) demonstrated that microinjections of VUF-8430 in the cerebellar vermis of mice impaired memory consolidation in two models of learning and emotional memory: the elevated plus maze (EPM), which is a model for assessing anxiety, and the IAT. A study by Sanna et al (8) in H4 receptor-knockout mice showed that these receptors modulate various neurophysiological functions, such as anxiety, locomotor activity, and nociception, indicating the importance of the integrity and functionality of the H4 receptors in the histaminergic regulation of neuronal functions.…”

“…Considering the results obtained by Fernandes et al (7) that VUF-8430 microinjection into the cerebellar vermis induced an inhibitory effect on memory consolidation in the EPM and IAT models, this study aimed to investigate whether VUF-8430 induces activation of CREB and phosphorylated CREB (pCREB) in the following structures: cerebellar vermis, prefrontal cortex (PFC), amygdala, and hippocampus.…”