Hypothalamic Histamine Release Research Articles

Central Histamine, the H3-Receptor and Obesity Therapy.

The brain histaminergic system plays a pivotal role in energy homeostasis, through H1- receptor activation, it increases the hypothalamic release of histamine that decreases food intake and reduces body weight. One way to increase the release of hypothalamic histamine is through the use of antagonist/inverse agonist for the H3-receptor. Histamine H3-receptors are auto-receptors and heteroreceptors located on the presynaptic membranes and cell soma of neurons, where they negatively regulate the synthesis and release of histamine and other neurotransmitters in the central nervous system. Although several compounds acting as H3-receptor antagonist/inverse agonists have been developed, conflicting results have been reported and only one has been tested as anti-obesity in humans. Animal studies revealed the opposite effect in food intake, energy expeditor, and body weight, depending on the drug, spice, and route of administration, among others. The present review will explore the state of art on the effects of H3-receptor ligands on appetite and body-weight, going through the following: a brief overview of the circuit involved in the control of food intake and energy homeostasis, the participation of the histaminergic system in food intake and body weight, and the H3-receptor as a potential therapeutic target for obesity.

Possible involvement of serotonin 5-HT2 receptor in the regulation of feeding behavior through the histaminergic system

The central histaminergic system has been proven to be involved in several physiological functions including feeding behavior. Some atypical antipsychotics like risperidone and aripiprazole are known to affect feeding behavior and to antagonize the serotonin (5-HT) receptor subtypes. To examine the possible neural relationship between the serotonergic and histaminergic systems in the anorectic effect of the antipsychotics, we studied the effect of a single administration of these drugs on food intake and hypothalamic histamine release in mice using in vivo microdialysis. Single injection of risperidone (0.5 mg/kg, i.p.) or aripiprazole (1 mg/kg, i.p.), which have binding affinities to 5-HT 1A, 2A, 2B and 2C receptors decreased food intake in C57BL/6 N mice with concomitant increase of hypothalamic histamine release. However, a selective D 2-antagonist, haloperidol (0.5 mg/kg, i.p.), did not have effects on food intake or histamine release. Furthermore, in histamine H 1 receptor-deficient mice, there was no reduction of food intake induced by atypical antipsychotics, although histamine release was increased. Moreover, selective 5-HT 2A-antagonists, volinanserin (0.5, 1 mg/kg, i.p.) and ketanserin (5, 10 mg/kg, i.p.), significantly increased histamine release and 5-HT 2B/2C -antagonist, SB206553 (2.5, 5 mg/kg, i.p.), slightly increased it. On the contrary, 5-HT 1A -selective antagonist, WAY100635 (1, 2 mg/kg), did not affect the histaminergic tone. These findings suggest that serotonin tonically inhibits histamine release via 5-HT 2 receptors and that antipsychotics enhance the release of hypothalamic histamine by blockade of 5-HT 2 receptors resulting in anorexia via the H 1 receptor.

Modanifil activates the histaminergic system through the orexinergic neurons

Modafinil is a drug used to treat hypersomnolence of narcolepsy. We previously reported that modafinil increases hypothalamic histamine release in rats but did not increase locomotor activity in histamine-depleted mice, suggesting that modafinil-induced locomotor activity involves the histaminergic system. Modafinil is also thought to express its effect through the orexinergic neurons, and orexin increases hypothalamic histamine release. These findings led us to investigate whether modafinil activates the histaminergic system via the orexinergic system. In the present study, we performed in vivo microdialysis and c-Fos immunohistochemistry to investigate whether the orexinergic system mediates the activation of the histaminergic system by modafinil using orexin neuron-deficient mice. Two hours after the injection, modafinil (150 mg/kg) caused a significant increase of histamine release compared to the basal release in wild type mice. However, modafinil had no effect on the histamine release in orexin neuron-deficient mice. By immunohistochemical study, we found that there was no neuronal activation in the tuberomammillary nucleus where the cell bodies of the histaminergic neurons exclusively exist in orexin neuron-deficient mice. These findings indicate that modafinil-induced increment of histamine release requires intact orexinergic neurons.

Acute central administration of immepip, a histamine H3 receptor agonist, suppresses hypothalamic histamine release and elicits feeding behavior in rats

Histamine suppresses feeding behavior via histamine H1 receptors in the hypothalamus. This study was performed to examine whether the acute reduction of histamine release in the hypothalamus caused by immepip, a histamine H3 agonist, modulates the feeding behavior of rats. Rats had a catheter implanted in the third cerebral ventricle (i3v) and were given central injections of phosphate-buffered-saline or immepip (100–300 pmol/rat). Following the i3v administration of immepip, the rats developed dose-dependent hypokinesia within 10 min of administration. Next to hypokinesia, the rats showed significant dose-dependent feeding behavior. High-performance liquid chromatography (HPLC) confirmed the reduction in histamine release in the hypothalamus of rats following i3v administration of immepip. These results suggest that i3v administration of immepip, an H3 receptor agonist, suppresses hypothalamic histamine release and elicits feeding behavior in rats.

Comparative effects of olanzapine and ziprasidone on hypophagia induced by enhanced histamine neurotransmission in the rat

Atypical antipsychotic drugs (AAPDs), such as olanzapine, are associated with weight gain and hyperphagia in both humans and rodents. This side effect, however, is absent or reduced for AAPD such as ziprasidone. The increased levels of appetite seen in rodents may be related to drug interactions with brain histamine systems involved in appetite control. We demonstrate a significant interaction of olanzapine treatment with histamine neurotransmission in a rat-feeding paradigm measuring the consumption of a palatable fat emulsion. This interaction was identified using the H3 receptor antagonist thioperamide, which by blocking autoreceptor control of histaminergic neurons enhances release of hypothalamic histamine, causing hypophagia. We challenged this effect of thioperamide with olanzapine, which among its pharmacological actions is a potent H1 receptor antagonist. Olanzapine pretreatment significantly attenuated thioperamide-induced hypophagia. Pretreatment of thioperamide with ziprasidone, an AAPD with negligible H1 receptor affinity, however, failed to have this effect. Although thioperamide may also increase levels of neurotransmitters other than histamine, the potent H1 antagonist property of olanzapine is likely to result in the suppression of thioperamide-induced hypophagia. We conclude that olanzapine may be directly modulating histaminergic neurotransmission associated with the regulation of feeding behaviour.

Comparison of the effect of an H 3-inverse agonist on energy intake and hypothalamic histamine release in normal mice and leptin resistant mice with high fat diet-induced obesity

Leptin is a key signal linking peripheral adiposity levels to the regulation of energy homeostasis in the brain. The injection of leptin decreases body weight and food intake in lean rodents; however, in a rodent model of high fat diet-induced obesity (DIO), the exogenous leptin cannot improve adiposity. This ineffectiveness is known as leptin resistance, and the factors downstream of leptin signaling have received attention as viable targets in the treatment of obesity. We previously reported that the histaminergic system is one of the targets of leptin. In the present study, the effect of an H 3-receptor inverse agonist on hypothalamic histamine release and energy intake was investigated in normal and DIO mice. Leptin (1.3 mg/kg, i.p.) significantly increased hypothalamic histamine release and reduced 12 h-energy intake in normal mice, but had no such effects in DIO mice. In contrast, clobenpropit (5 mg/kg, i.p.), an H 3-inverse agonist, elicited a significant increase in histamine release in both types of mice. Clobenpropit did not reduce 12 h-energy intake; however, it decreased 3 h-energy intake in both types of mice. These results suggest that lack of the activation of the histaminergic system partly contributes to obesity in DIO mice and direct activation of the histaminergic system circumvents leptin resistance.

A role of the histaminergic system for the control of feeding by orexigenic peptides

A considerable number of neuropeptides are involved in the hypothalamic regulation of feeding behavior. We previously reported that leptin, the ob gene product, expressed its anorectic effect though the histaminergic system via histamine H 1 receptors. However, the interactions among the orexigenic neuropeptides, such as orexin-A, neuropeptide Y (NPY), and ghrelin, and the histaminergic system have not yet been clarified. In this study, we investigated the effect of the neuropeptides on the hypothalamic histamine release in rats, and on food intake and locomotor activity in H 1-receptor knockout (H1R-KO) mice. Orexin-A increased the histamine release and locomotor activity, but not food intake, suggesting that the histaminergic system participates in arousal rather than feeding by orexin-A. NPY also increased histamine release, but its effect was not immediate. NPY-injected H1R-KO mice consumed more food than the wild-type mice; thus, the histaminergic system may act as a feedback factor downstream of NPY. Ghrelin did not affect histamine release, and it increased food intake, even in H1R-KO mice. Thus, ghrelin expresses its action in a histamine-independent manner.

Hypothalamic histamine release by taste stimuli in freely moving rats: Possible implication of palatability

Our previous study indicated that taste information via the chorda tympani (CT) activates the central histaminergic system in anesthetized rats. However, the physiological roles of taste-induced histamine release remain unknown, thus to further investigate the relationship between histamine release and gustatory information, in the present study we investigated the effect of taste stimuli infused intraorally on histamine release using in vivo microdialysis in free moving rats. Consistent with findings from our previous study, application of NaCl and HCl caused significant increases in histamine levels further supporting the suggestion that this phenomenon is attributed to the excitation of the CT. When rats were intraorally infused with quinine HCl (QHCl) solution, a significant increase in hypothalamic histamine release was observed. On the other hand, histamine release was decreased by sucrose and saccharin solutions. When rats were conditioned to acquire taste aversion to sucrose solution or saccharin solution, instead of the histamine decrease seen by the palatable solutions, the pattern of histamine release was similar to that seen by QHCl solution. From these observations, it is concluded that the histamine release by the infusion of these tastants may be explained by two mechanisms—by causing a transient increase after taste stimulation and by causing a decrease relative to the tastant's palatability.

Modafinil increases histamine release in the anterior hypothalamus of rats

Modafinil, ( RS)-2-(Diphenylmethylsulfinyl)acetamide, is a well known wake promoting drug used for the treatment of narcolepsy. We investigated the effect of modafinil on the hypothalamic histamine release in the anesthetized rat using in vivo microdialysis. Modafinil (150 mg/kg, i.p.) increased histamine release by 150% of the basal release. The intracerebroventricular (i.c.v.) injection of modafinil (1 nmol) also increased histamine release, however, when modafinil (1 nmol) was injected directly into the tuberomammillary nucleus, a limited region where cell bodies of the histaminergic neurons are located, histamine release was not altered. These observations suggest that modafinil may promote waking via the activation of the histaminergic system, although it does not appear to be a direct pharmacological target of modafinil.

The effect of taste stimuli on histamine release in the anterior hypothalamus of rats

We studied the effect of gustatory stimulation on hypothalamic histamine release. Administering a four-basic taste mixture significantly increased histamine release, but not in the chorda tympani-transected rats. 0.1 M NaCl significantly increased histamine release, whereas 0.5 M sucrose, 0.02 M quinine HCl and 0.01 M HCl had no effect. However, when the concentration of HCl was increased to 0.03 M, a significant increase in histamine release was seen. These results suggest that taste information via the chorda tympani activates the histaminergic system.

The effect of orexin-A and -B on the histamine release in the anterior hypothalamus in rats

The neuropeptides orexin-A and -B have been reported to be appetite-stimulating peptides, but they are also known as important factors that control arousal state. We studied the effects of orexin-A and -B on the hypothalamic histamine release using in vivo microdialysis. A significant and sustained increase in histamine release was observed by intracerebroventricular injection of 1 nmol of orexin-A, but not by the same dose of orexin-B. An increased dose of orexin-B to 5 nmol facilitated histamine release, although this effect was much less potent than orexin-A. These findings suggest that both of the orexins play important roles in the regulation of waking through the activation of histaminergic system.

The role of the chorda tympani nerve in the activation of the rat hypothalamic histaminergic system by leptin

A possible pathway through which leptin activates the histaminergic system was studied using in vivo microdialysis in rats. Intraperitoneal injection of leptin (1.3 mg/kg) caused a significant increase in hypothalamic histamine release, however, its intracerebroventricular injection (10 μg/rat) did not cause any significant changes in the release. Furthermore, leptin (1.3 mg/kg) had no effect on histamine release in rats whose chorda tympani nerves, a branch of the facial nerve which mediates taste information, were transected bilaterally. These findings indicate that leptin activates the histaminergic system by the peripheral signal inputs via the chorda tympani resulting in the suppression of food intake.

P-426 - The effect of leptin on the hypothalamic histamine release

P-426 - The effect of leptin on the hypothalamic histamine release

Prostaglandin E2 mediates activation of hypothalamic histamine by interleukin-1beta in rats.

The present study was designed to investigate the effects of peripheral interleukin-1beta (IL-1beta) on hypothalamic histamine (HA) systems. Intraperitoneal injection of IL-1beta increased the turnover rate of hypothalamic HA, which was assessed by accumulation of tele-methylhistamine after pargyline treatment. IL-1beta increased the activities of both histidine decarboxylase (HDC), an HA synthesizing enzyme, and HA-N-methyltransferase (HMT), an HA catabolizing enzyme. Pretreatment with indomethacin completely blocked the effects induced by IL-1beta on hypothalamic HA. Infusion of prostaglandin E2 (PGE2) into the third cerebroventricle increased the hypothalamic HA turnover rate, and simultaneously activated both HDC and HMT dose-dependently, but intravenous infusion of PGE2 had no effect on the dynamics of hypothalamic HA turnover. These results indicate that hypothalamic PGE2 activated by peripheral administration of IL-1beta, but not by peripheral PGE2, may enhance synthesis and release of hypothalamic HA by activation of HDC, and may facilitate degradation of extracellular histamine by activation of HMT.

In vivo modulation of rat hypothalamic histamine release by the histamine H 3 receptor ligands, immepip and clobenpropit. Effects of intrahypothalamic and peripheral application

We investigated the effect of the new potent and selective histamine H 3 receptor agonist, immepip, and the histamine H 3 receptor antagonist, clobenpropit, on in vivo neuronal histamine release from the anterior hypothalamic area of urethane-anesthetized rats, using microdialysis. Intrahypothalamic perfusion with immepip at concentrations of 1 and 10 nM reduced histamine release to 75% and 35% of its basal level, respectively. Peripheral injection of immepip (5 mg/kg) caused a sustained decrease in histamine release of 50%. Clobenpropit potently increased histamine release after intrahypothalamic perfusion. The maximal increase in histamine release was 2-fold, observed at a concentration of 10 nM clobenpropit. Peripheral injection of clobenpropit (5–15 mg/kg) increased histamine release to about 150% of the basal value. A more marked increase in histamine release was found after injection of the histamine H 3 receptor antagonist, thioperamide (5 mg/kg). In conclusion, intrahypothalamic perfusion of the histamine H 3 receptor agonist, immepip and the histamine H 3 receptor antagonist, clobenpropit, potently and oppositely modulated in vivo histamine release from the anterior hypothalamic area. The decreased histamine release after peripheral injection of immepip indicates that this novel agonist readily crosses the blood–brain barrier, making it a potential candidate for in vivo histamine H 3 receptor studies. The differential increase in histamine release after peripheral injection of clobenpropit and thioperamide is discussed.

Hypothalamic Histamine Release in Normal and Stressed Rats Is Affected by Sex and Aging

Changes in the baseline and in the 40 mM K +-evoked release of histamine from hypothalamus slices were compared in male and female rats aged 2, 6, 12, 18, and 24 months. The baseline release declined in the 12-, 18-, and 24-month males. In contrast, the K +-evoked release remained constant in the males, but in the females it decreased in animals more than 2 months old. The efficiency of the H 3 receptors was also determined by measuring the reduction of the K +-evoked release induced by the H 3 receptor agonist (R)-alpha-methylhistamine. This substance significantly decreased the amount of HA released in all age groups, except the 24-month-old males. Histamine release was also measured after exposure to a weak electrical stress. In 2- and 6-month-old males, there was a marked reduction of both the baseline and the K +-evoked release, and also of the inhibitory effect of the H 3 agonist. There were no changes in the 12- and 18-month age groups, but both releases were enhanced in the 24-month group. In females, electrical stress had no significant effect, except in the youngest age group. Stress-dependent release of plasma corticosterone was decreased in males older than 12 months and in females older than 6 months. These changes gave a good correlation with variation in the H 3 receptors. This study, therefore, demonstrates that aging modifies, in a sex-dependent way, the basal and stress-stimulated functions of the hypothalamic presynaptic histaminergic neurons.

Hypothalamic neuronal histamine modulates physiological responses induced by interleukin-1 beta.

Dynamic involvement of hypothalamic histamine in ingestive behavior and thermogenesis induced by interleukin-1 beta (IL-1 beta) was examined in rats. Intraperitoneal injection of 0.12 nmol/rat IL-1 beta decreased food and water intake and elevated body temperature. However, depletion of neuronal histamine induced by intraperitoneal injection of 160 mumol/rat alpha-fluoromethylhistidine, a suicide inhibitor of histidine decarboxylase (HDC), attenuated the suppressive effect of IL-1 beta on food intake, facilitated the suppressive effect on drinking, and enhanced the elevating effect on rectal temperature. Intraperitoneal injection of 0.12 nmol/rat IL-1 beta increased hypothalamic histamine turnover rate. The same dose of IL-1 beta also increased activity of HDC and histamine-N-methyltransferase (HMT). These results suggest that IL-1 beta may stimulate synthesis and release of hypothalamic histamine in presynaptic terminals by activation of HDC and facilitate degradation of extracellular histamine by activation of MHT. These changes in the dynamics of hypothalamic histamine modulate IL-1 beta-induced ingestive behavior and body temperature.

Effects of a selective α2-adrenoceptor antagonist, atipamezole, on hypothalamic histamine and noradrenaline release in vivo

In vivo microdialysis was used to study the effects of a potent and selective α 2-adrenoceptor antagonist, atipamezole, on histamine and noradrenaline release from the medial hypothalamus in anesthetized rats. Local perfusion with atipamezole via the microdialysis probe increased histamine release significantly and dose-dependently. However, the effect of systemic administration of atipamezole (1 mg/kg) was opposite: it significantly decreased histamine release. Local and systemic administration of atipamezole produced an approx. 2-fold increase in noradrenaline release. To study the modulatory effect of noradrenergic neurons on histamine release, noradrenaline synthesis was inhibited with α-methyl- p-tyrosine. In the microdialysis experiment, rats that received α-methyl- p-tyrosine exhibited to decrease, but rather a slight increase in histamine release in response to systemic atipamezole administration. These results show clearly that atipamezole enhances noradrenaline release in vivo from rat hypothalamus and its effects on histamine release are dependent on the route of drug administration.

Endogenous serotonin modulates histamine release in the rat hypothalamus as measured by in vivo microdialysis

In vivo microdialysis was used to study the effects of serotonergic drugs on histamine release from the suprachiasmatic nuclei region of the anterior hypothalamus in anesthetized rats. Local perfusion with serotonin (5-hydroxytryptamine, 5-HT) increased histamine release significantly and dose dependently. Methysergide (10 mg/kg i.p.), a 5- HT 2C 2A receptor antagonist, given 30 min before 5-HT perfusion, blocked the 5-HT-evoked histamine release. Methysergide (10 mg/kg i.p.), given alone, also suppressed basal histamine release by 33%. Dexfenfluramine (10 μM), a 5-HT releaser and uptake blocker, administered via the microdialysis probe, significantly enhanced hypothalamic histamine release. With the same dose of dexfenfluramine, 5-HT releasc increased 10-fold in the same brain area. These results show for the first time that endogenous 5-HT modulates histamine release in vivo and it has a tonic stimulatory effect on the histaminergic nerve terminals of the rat anterior hypothalamus.

Vestibular modulation of the septo-hippocampal cholinergic system of rats.

Effects of vestibular stimulation on the in vivo release of hypothalamic histamine and hippocampal acetylcholine (ACh) were investigated in urethan-anesthetized rats, using a brain microdialysis method. Changes in glutamate concentration in the medial vestibular nucleus (MVN) were also monitored by a microbiosensor technique using a glutamate oxidase-embodied platinum electrode. Caloric stimulation with hot water increased the glutamate release in the MVN, while that with ice water decreased it. It is evidenced that glutamate is a neurotransmitter between afferent vestibular nerve and the MVN. Electrical stimulation of the round window evoked the release of hypothalamic histamine and hippocampal ACh and these effects were inhibited by the blockade of second-order vestibular neurons by the pre-injection of 6,7-dinitroquinoxaline-2,3-dione (DNQX), an antagonist of non-N-methyl-D-aspartate (non-NMDA) glutamate receptors, into the ipsilateral vestibular nucleus. Caloric stimulation with both hot and ice water increased the release of hypothalamic histamine and hippocampal ACh. It is suggested that both the histaminergic and cholinergic systems were activated by the imbalance of intervestibular activities. Depletion of neuronal histamine by alpha-fluorometylhistidine (FMH), an irreversible inhibitor of histamine synthesis, did not suppress the vestibular evoked release of hippocampal ACh. In contrast, caloric stimulation did not evoke hypothalamic histamine release in rats treated with ethylcholine aziridiniun ion (AF64A), a putative cholinotoxin. All these findings suggest that the vestibular information activated the histaminergic neurons via the activation of the cholinergic neurons and this neuronal circuit was involved in the vestibulo-autonomic response.