The Effects of Histaminergic Agents in the Nucleus Accumbens of Rats in the Elevated Plus-Maze Test of Anxiety

Article excerpt

Objective: The nucleus accumbens (NAc) receive histaminergic neurons from tuberomammillary nuclei. There are reports indicating that central histamine systems are involved in many physiological behavioral processes, including anxiety. The aim of the present study was to assess whether the histaminergic system of the NAc is involved in anxiety-related behaviors.

Methods: Rats were anesthetized with intra-peritoneal injection of ketamine hydrochloride, plus xylazine and then were placed in a stereotaxic apparatus. In addition, two stainless-steel cannuale were placed 2 mm above the nucleus accumbens shell. Seven days after recovery from surgery, the behavioral testing was started. As a model of anxiety, the elevated plus maze which is a useful test to investigate the effects of anxiogenic or anxiolytic drugs in rodents, was used in male Wistar rats.

Results: Intra-NAc administration of histamine (0.01, 0.1 and 1 µg/rat) increased the percentage of open arm time (%OAT) and open arm entries (%OAE) ,but not locomotor activity, indicating an anxiolytic response. Furthermore, bilateral microinjections of different doses of the H1 receptor antagonist pyrilamine (0.001, 0.01, 0.1 and 1 µg/rat) or the H2 receptor antagonist ranitidine (0.001, 0.01, 0.1 and 1 µg/rat) into the NAc increased %OAT and %OAE , but not locomotor activity. However, both histamine and histamine receptor antagonists showed an anxiolytic-like effect ; the antagonists (1 µg/rat) also decreased the histamine response.

Conclusion: The results may indicate a modulatory effect for the H1 and H2 histamine receptors of nucleus accumbens in the anxiety behavior of rats.

Keywords: Anxiety, Histamine, Maze learning ,Pyrilamine, Ranitidine, Rats

Iran J Psychiatry 2010; 5:11-17

Histamine as a neurotransmitter may be involved in a wide range of physiological functions (for review see (1)), including learning and memory (2), morphinestate dependent learning (3) and novel environment motivated exploration (4, 5). Neuronal histamine increases emotional reactivity to aversive stimulation, which might increase learning motivation in avoidance and escape tasks (6). The involvement of the histaminergic system in the modulation of anxietyrelated behaviors in animals has been suggested previously (7, 8). It has been shown that the histamine administration into the central amygdala may induce an anxiogenic response (9). On the other hand, anxietyrelated stress may release histamine (10). Histamine may also be involved in the modulation of nucleus accumbens neurons (11).

Histamine acts through different receptor subtypes namely: H1, H2 and H3 receptors. The H1 receptors are a G-protein family of receptors whose activation leads to stimulation of phospholipase C and increase in cAMP levels (12). The H2 receptors are G-protein coupled receptors (13) whose activation leads to enhanced production of cAMP (14). The histamine H3 receptor is an autoreceptor, regulating the release and synthesis of histamine (15). It has been shown that high densities of histamine H1 receptors are present in the limbic system, including several hippocampal areas (1). Those mice lacking histamine H1 receptors showed prolonged transfer latency in the light/dark box test indicating that the mutant mice were less fearful than the wild-type mice (16).

Although behavioral effects of histamine and related compounds have been evaluated in some brain regions [such as the dorsal and ventral hippocampus (17-19), the central amygdala (9), the nucleus accumbens (20), the inferior colliculus, the periaqueductal gray (21) and the nucleus basalis magnocellularis (7)], its influences on anxiety in the nucleus accumbens (NAc) have not been evaluated yet. The aim of the present study was to investigate the effects of histamine and histamine H1 and H2 receptor antagonists microinjected into the NAc and their possible roles in the modulation of anxietyrelated behaviors using the elevated plus-maze test of anxiety in rats. …