Hypothalamic Histamine Research Articles

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.

Time course of thyroxine on hypothalamic histamine in the rat

Time course of thyroxine on hypothalamic histamine in the rat

Influence of a selective histamine H3 receptor antagonist on hypothalamic neural activity, food intake and body weight

This study was conducted to elucidate whether antagonistic targeting of the histamine H3 receptor increases hypothalamic histamine levels, in parallel with decreases in food intake and body weight. The competitive antagonist potency of a recently synthesized histamine H3 receptor antagonist, NNC 38-1049, was studied in intact HEK293 cells expressing human or rat histamine H3 receptor, in which NNC 38-1049 was allowed to antagonize the effect of the H3 receptor agonist R-alpha-methylhistamine on isoprenaline-induced accumulation of cAMP. The affinity of NNC 38-1049 for a number of variants of the histamine receptor was also determined. Following single dosing of normal rats with NNC 38-1049, hypothalamic histamine levels were assessed by means of microdialysis. Plasma and brain levels of NNC 38-1049 and acute effects on food intake and energy expenditure were followed after oral doses of 3-60 mg/kg. Potential side effects were examined with rat models of behaviour satiety sequence (BSS), pica behaviour and conditioned taste aversion (CTA). Intakes of food and water together with body weight were recorded for 15 days during daily dosing of dietary obese rats. NNC 38-1049 was found to be a highly specific and competitive antagonist towards both human and rat histamine H3 receptors, and measurable amounts of NNC 38-1049 were found in the plasma of rats following single oral doses of 3-60 mg/kg and in the brain after 15-60 mg/kg. Following single intraperitoneal injections of NNC 38-1049 (20 mg/kg), significant increases in extracellular histamine concentrations were observed. The same dose did not change BSS or pica behaviour acutely, nor did it induce CTA following repeated administration for 7 days. Reductions in food intake were seen very soon after administration, and occurred in a dose-dependent fashion. Energy expenditure was unchanged, but the respiratory quotient (RQ) tended to decrease at higher doses, indicating an increase in lipid oxidation. Twice daily administration of 20 mg/kg of NNC 38-1049 in old and dietary obese rats resulted in sustained reduction of food intake throughout a 2-week study, and was associated with a highly significant (P<0.01) decrease in body weight compared with controls (-18.4+/-3.4 vs +0.4+/-2.7 g). The same dose of NNC 38-1049 produced an acute decrease of water intake, but 24 h intakes were not significantly changed. The results of this study strongly support the idea that an increase in the hypothalamic concentration of histamine produces a specific reduction of food intake and that this effect can be translated into a decrease in body weight.

Preclinical Pharmacology of FMPD [6-Fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene]: A Potential Novel Antipsychotic with Lower Histamine H1Receptor Affinity Than Olanzapine

FMPD [6-fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene] is a potential novel antipsychotic with high affinity for dopamine D2 (Ki= 6.3 nM), 5-HT(2A) (Ki= 7.3 nM), and 5-HT6 (Ki= 8.0 nM) human recombinant receptors and lower affinity for histamine H1 (Ki= 30 nM) and 5-HT2C (Ki= 102 nM) human recombinant receptors than olanzapine. Oral administration of FMPD increased rat nucleus accumbens 3,4-dihyroxyphenylacetic acid concentrations (ED200 = 6 mg/kg), blocked 5-HT2A agonist-induced increases in rat serum corticosterone levels (ED50= 1.8 mg/kg), and inhibited the ex vivo binding of [125I]SB-258585 [4-iodo-N-[4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-benzenesulfonamide] to striatal 5-HT6 receptors (ED50= 10 mg/kg) but failed to inhibit ex vivo binding of [3H]pyrilamine to hypothalamic histamine H1 receptors at doses of up to 30 mg/kg. In electrophysiology studies, acute administration of FMPD selectively elevated the number of spontaneously active A10 (versus A9) dopamine neurons and chronic administration selectively decreased the number of spontaneously active A10 (versus A9) dopamine neurons. FMPD did not produce catalepsy at doses lower than 25 mg/kg p.o. In Fos-induction studies, FMPD had an atypical antipsychotic profile in the striatum and nucleus accumbens and increased Fos expression in orexin-containing neurons of the hypothalamus. FMPD produced only a transient elevation of prolactin levels. These data indicate that FMPD is an orally available potent antagonist of dopamine D2, 5-HT2A, and 5-HT6 receptors and a weak antagonist of H1 and 5-HT2C receptors. FMPD has the potential to have efficacy in treating schizophrenia and bipolar mania with a low risk of treatment-emergent extrapyramidal symptoms, prolactin elevation, and weight gain. Clinical trials are needed to test these hypotheses.

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.

Hypothalamic Neuronal Histamine Modulates Febrile Response but Not Anorexia Induced by Lipopolysaccharide

This study examined the contribution of hypothalamic neuronal histamine (HA) to the anorectic and febrile responses induced by lipopolysaccharide (LPS), an exogenous pyrogen, and the endogenous pyrogens interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). Intraperitoneal (ip) injection of LPS, IL-1beta, or TNF-alpha suppressed 24-hr cumulative food intake and increased rectal temperature in rats. To analyze the histaminergic contribution, rats were pretreated with intracerebroventricular (icv) injection of 2.44 mmol/kg or ip injection of 244 mmol/kg of alpha-fluoromethylhistidine (FMH), a suicide inhibitor of histidine decarboxylase (HDC), to deplete neural HA. The depletion of neural HA augmented the febrile response to ip injection of LPS and IL-1beta and alleviated the anorectic response to ip injection of IL-1beta. However, the depletion of neural HA did not modify the LPS-induced anorectic response or TNF-alpha-induced febrile and anorectic responses. Consistent with these results, the rate of hypothalamic HA turnover, assessed by the accumulation of tele-methylhistamine (t-MH), was elevated with ip injections of LPS and IL-1beta, but unaffected by TNF-alpha at equivalent doses. This suggests that (i) LPS and IL-1beta activate hypothalamic neural HA turnover; (ii) hypothalamic neural HA suppresses the LPS- and IL-1beta-induced febrile responses and accelerates the IL-1beta-induced anorectic response; and (iii) TNF-alpha modulates the febrile and anorectic responses via a neural HA-independent pathway. Therefore, hypothalamic neural HA is involved in the IL-1beta-dominant pathway, rather than the TNF-alpha-dominant pathway, preceding the systemic inflammatory response induced by exogenous pyrogens, such as LPS. Further research on this is needed.

Hypothalamic histamine levels in hyperthyroid, arthritic and C48/80-treated rats

Hypothalamic histamine levels in hyperthyroid, arthritic and C48/80-treated rats

Involvement of hypothalamic histamine H1 receptor in the regulation of feeding rhythm and obesity.

Histamine H(1) receptors (H(1)-Rs) are found in peripheral tissues and in regions of the hypothalamus that are concerned with regulating body composition. In the present study, we investigated the detailed mechanisms of histamine H(1)-Rs in the development of obesity. Histamine H(1)-R knockout (H1KO) mice gradually developed mature-onset obesity, which was accompanied by hyperphagia and decreased expression of uncoupling protein-1 (UCP-1) mRNA. Both younger nonobese (12-week-old) and older obese (48-week-old) H1KO mice exhibited impairment of the responsiveness to the leptin. In addition, disruption of the diurnal rhythm of feeding occurred before the onset of obesity in H1KO mice. Correction of these abnormal feeding rhythms by means of scheduled feeding caused a reduction in obesity and associated metabolic disorders in H1KO mice. Furthermore, central administration of a histamine H(1)-R agonist affected feeding behavior, body weight, and c-fos-like immunoreactivity in the hypothalamus. Taken together, these findings suggest that histamine H(1)-Rs are crucial for the regulation of feeding rhythm and in mediating the effects of leptin. Early disruption of H(1)-R-mediated functions in H1KO mice may lead to hyperphagia and decreased expression of UCP-1 mRNA, which may contribute to the development of obesity in these animals. In addition, centrally acting histamine H(1)-R may be a novel therapeutic target for the treatment of obesity and related metabolic disorders.

High leptin level is accompanied with decreased long leptin receptor transcript in histamine deficient transgenic mice

Leptin is a multifunctional cytokine and hormone that primarily acts in the hypothalamus and plays a key role in regulation of food intake and energy expenditure. Leptin acts through its receptor (OBR), the product of db gene that activates the Jak/STAT pathway predominantly. To exert its functions, leptin interacts with histamine as well. Histamine is a downstream effector of leptin as its release, metabolism is enhanced by leptin and hypothalamic histamine reduces food intake. In a bi-directional regulatory loop histamine also influences leptin concentration by inhibiting its expression. In this study we demonstrate that histamine deficiency elevates serum leptin level and decreases full-length leptin receptor isoform with a slight increase of the short one and results in mild late onset obesity. These observation can help to elucidate further the bi-lateral interaction of leptin and histamine, and therefore provide useful data to understand the pathomechanism of obesity.

Hypothalamic neuronal histamine in genetically obese animals: its implication of leptin action in the brain.

Leptin regulates feeding behavior and energy metabolism by affecting hypothalamic neuromodulators. The present study was designed to examine hypothalamic neuronal histamine, a recently identified mediator of leptin signaling in the brain, in genetic obese animals. Concentrations of hypothalamic histamine and tele-methylhistamine (t-MH), a major histamine metabolite, were significantly lower in obese (ob/ob) and diabetic (db/db) mice, and Zucker fatty (fa/fa) rats, leptin-deficient and leptin-receptor defective animals, respectively, relative to lean littermates (P < 0.05 for each). A bolus infusion of leptin (1.0 microg) into the lateral ventricle (ilvt) significantly elevated the turnover rate of hypothalamic neuronal histamine, as assessed by pargyline-induced accumulation of t-MH, in ob/ob mice compared with phosphate-buffered saline (PBS) infusions (P < 0.05). However, this same treatment did not affect hypothalamic histamine turnover in db/db mice. In agouti yellow (A(y)/a) mice, animals defective in pro-opiomelanocortin (POMC) signaling, normal levels of histamine, and t-MH were seen in the hypothalamus at 4 weeks of age when obesity had not yet developed. These amine levels in A(y)/a mice showed no change until 16 weeks of age, although the mice were remarkably obese by this time. Infusions of corticotropin releasing hormone (CRH), one of neuropeptide related to leptin signaling, into the third ventricle (i3vt) increased histamine turnover in the hypothalamus of Wistar King A rats (P < 0.05 versus PBS infusion). Infusion of neuropeptide Y (NPY) or alpha-melanocyte stimulating hormone (MSH), a POMC-derived peptide failed to increase histamine turnover. These results indicate that lowered activity of hypothalamic neuronal histamine in ob/ob and db/db mice, and fa/fa rats may be due to insufficiency of leptin action in the brains of these animals. These results also suggest that disruption of POMC signaling in A(y)/a mice may not impact on neuronal histamine. Moreover, CRH but neither POMC-derived peptide nor NPY may act as a signal to neuronal histamine downstream of the leptin signaling pathway.

Hyperleptinemia, Visceral Adiposity, and Decreased Glucose Tolerance in Mice with a Targeted Disruption of the Histidine Decarboxylase Gene

Histamine has been referred to as an anorexic factor that decreases appetite and fat accumulation and affects feeding behavior. Tuberomammillary histaminergic neurons have been implicated in central mediation of peripheral metabolic signals such as leptin, and centrally released histamine inhibits ob gene expression. Here we have characterized the metabolic phenotype of mice that completely lack the ability to produce histamine because of targeted disruption of the key enzyme in histamine biosynthesis (histidine decarboxylase, HDC). Histochemical analyses confirmed the lack of HDC mRNA, histamine immunoreactivity, and histaminergic innervation throughout the brain of gene knockout mouse. Aged histamine-deficient (HDC-/-) mice are characterized by visceral adiposity, increased amount of brown adipose tissue, impaired glucose tolerance, hyperinsulinemia, and hyperleptinemia. Histamine-deficient animals are not hyperphagic but gain more weight and are calorically more efficient than wild-type controls. These metabolic changes presumably are due to the impaired regulatory loop between leptin and hypothalamic histamine that results in orexigenic dominance through decreased energy expenditure, attenuated ability to induce uncoupling protein-1 mRNA in the brown adipose tissue and defect in mobilizing energy stores. Our results further support the role of histamine in regulation of energy homeostasis.

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 role of hypothalamic histamine in leptin-induced suppression of short-term food intake in fasted rats

Objective: Leptin suppresses food intake; however, the precise mechanism is not fully understood. Histamine (HA), which acts as a neurotransmitter in the central nervous system, has also been shown to be involved in feeding and exerts an inhibitory effect through activation of H 1 receptors. Therefore, we studied the possible role of HA in short-term leptin-induced suppression of food intake. Methods: We studied the 6-h feeding response of overnight-fasted adult (200 g) male Wistar rats to leptin and the HA synthesis inhibitor α-fluoromethylhistidine (α-FMH). Levels of transcription for neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH), as well as hypothalamic content of HA and the HA metabolite telemethyl-HA were investigated. Results: Central administration of leptin (3, 5 and 10 μg at 09:00 h) in fasted rats caused a decrease in food intake. In contrast, central administration of α-FMH (11, 22 and 112 μg at 09:00 h) increased food intake. Prior administration of α-FMH prevented the leptin-induced decrease in food intake. Leptin decreased hypothalamic histamine content, while increasing the ratio between telemethyl-HA and HA, indicating that leptin reduces HA metabolism. Finally, α-FMH suppressed basal and leptin-induced CRH expression while stimulating NPY expression in fasted rats. Conclusion: Histamine is involved in leptin-induced inhibition of food intake. The role of histamine may be mediating, i.e. leptin may directly activate and/or change the metabolism of the histaminergic system. Alternatively, the histaminergic system may be involved in a permissive manner.

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.

Histamine H 1 receptors in the ventromedial hypothalamus mediate the anorectic action of the pancreatic hormone amylin

In the present study we investigated the role of hypothalamic histamine H 1 receptors in the mediation of peripheral amylin’s anorectic effect. Rats with chronically implanted bilateral cannulas were infused into the ventromedial hypothalamus (VMH) with the specific histamine H 1 receptor antagonists pyrilamine (PYR, 104 nmol/rat) or chlorpheniramine (CPA, 52 nmol/rat), respectively, combined with an intraperitoneal (IP) injection of amylin (5 μg/kg). Amylin’s inhibitory effect on food intake (i.e. 50% reduction in cumulative food intake 30 min after ingestion) was markedly reduced by CPA and PYR (e.g. amylin and CPA: 5% reduction versus control). We therefore suggest an important role of hypothalamic H 1 receptors in the signal transduction of peripheral amylin’s anorectic action.

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.

Hypothalamic histamine neurons activate lipolysis in rat adipose tissue.

The contribution of hypothalamic histamine neurons to the central regulation of peripheral lipid metabolism was investigated in rats using in vivo microdialysis system. A bolus infusion of L-histamine at doses of 10--10(3) nmol/rat into the third cerebral ventricle (i3vt) dose-dependently increased glycerol concentration in the perfusate from the epididymal adipose tissue. I3vt infusion of 10(2) nmol/rat thioperamide, an autoinhibitory H(3) receptor antagonist that activates histamine neurons to increase synthesis and release of neuronal histamine, convincingly mimicked histamine action in the augmented lipolysis. Intraperitoneal pretreatment with propranolol, a beta-adrenoceptor antagonist, abolished the thioperamide-induced lipolytic action. An electrophysiological study demonstrated that efferent sympathetic nerves innervating the epididymal fat were activated after the i3vt infusion of thioperamide. Hypothalamic histamine neurons thus regulate peripheral lipid metabolism through the accelerating lipolytic action by activation of sympathetic beta-adrenoceptor.

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.

An acute i.c.v. infusion of leptin has no effect on hypothalamic histamine and tele-methylhistamine contents in Wistar rats

The actions of intracerebroventricularly (i.c.v.) infused leptin on food intake, body weight and hypothalamic contents of histamine and tele-methylhistamine, the main histamine metabolite in the mammalian brain, were studied in male Wistar rats. The effect of the histamine H 1 receptor blockade on leptin-induced anorexia was also examined. It was found that leptin at the dose of 10 μg i.c.v. reduced 24-h food intake by 48% as compared with the controls ( P<0.01). This leptin dose reduced feeding during 2–4 consecutive days. In spite of the marked changes in food consumption and body weight gain, leptin did not alter the hypothalamic contents of histamine and tele-methylhistamine. Furthermore, the blockade of histamine H 1 receptors by mepyramine did not attenuate the effect of leptin on feeding and body weight. The findings indicate that centrally administered leptin suppresses feeding and promotes weight loss through mechanisms that do not require the direct participation of the brain histaminergic neuron system.

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

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