Hypothalamic Histamine Research Articles

A very-low-calorie conventional Japanese diet: its implications for prevention of obesity.

A very-low-calorie conventional Japanese diet of 370 kcal/day has been shown to be useful for weight reduction and its long-term maintenance. Sources of the diet were mainly from chicken fillet, egg white, fish white-meat, mushroom, seaweed and low- or non-calorie fiber-rich vegetable, and contained 4.4g fat, 38.1g protein, 45.2g carbohydrate and essential minerals and vitamins. However, metabolic and neural implications of a commercial very-low-calorie liquid formula diet have rarely been investigated from the view point of food intake and appetite regulation. Animal studies have demonstrated the rationale for efficacy of the very-low calorie conventional Japanese diet as follows: (1) Increased hypothalamic histamine suppressed food intake through H1-receptors in the ventromedial hypothalamus (VMH) and paraventricular nucleus, the satiety centers. (2) Low energy intake enhanced satiety and decreased food intake through histaminergic activation of VMH neurons. (3) Mastication activated afferent signal transmission from proprioceptors in the oral cavity to the mesencephalic trigeminal nucleus(Me5). Histaminergic systems in the hypothalamus were activated by mastication and low energy supply, which was accompanied by satiation through the action of histamine in the VMH. Usefulness of the very-low-calorie conventional Japanese diet derives from utilization of conventional Japanese food stuffs as a fiber rich, low energy food source, and from enhancement of satiation by increased mastication required of the diet. The properties of the diet seemed to effect a closed positive feedback loop between histaminergic activation in hypothalamic satiety centers and behavioral changes to enhance satiation and cause feeding suppression.

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.

The effect of metoprine on glucoprivic feeding induced by 2-deoxy- D-glucose

Metoprine is a histamine N-methyltransferase inhibitor that elevates endogenous histamine (HA) levels. Because the histaminergic mechanism may be involved in the regulation of feeding behavior as well as in body glucose homeostasis, the effect of metoprine on glucoprivic feeding was studied in Wistar rats. Although metoprine treatment (10 and 20 mg/kg, IP) decreased feeding, the rats still responded to the administration of 400 mg/kg of 2-deoxy- D-glucose (2-DG) by increasing their feed intake. No difference was seen in the 6-h cumulative feed intake after administration of 2-DG between the metoprine- and solvent-treated rats. However, the response was delayed, and with 20 mg/kg metoprine the feed intake was significantly reduced during 2 h after 2-DG application. Both 2-DG and metoprine elevated plasma glucose concentration despite their opposite effects on feeding. Hypothalamic HA or its metabolite levels were not affected by 2-DG. The results suggest that the effects of metoprine and 2-DG are largely independent of each other, and that the feeding modulating function of HA is on such a level that it does not prevent the glucoprivic emergency response.

Prostaglandin E2 mediates activation of hypothalamic neuronal histamine by interleukin-1β in rats

Prostaglandin E2 mediates activation of hypothalamic neuronal histamine by interleukin-1β in rats

Dehydration-induced release of vasopressin involves activation of hypothalamic histaminergic neurons.

The hypothalamic neurotransmitter histamine (HA) induces arginine vasopressin (AVP) release when administered centrally. We studied and characterized this effect of HA with respect to receptor involvement. In addition, we studied the possible role of hypothalamic histaminergic neurons in the mediation of a physiological stimulus (dehydration) for AVP secretion. Intracerebroventricular administration of HA, the H1-receptor agonists 2(3-bromophenyl)HA and 2-thiazolylethylamine, or the H2-receptor agonists amthamine or 4-methyl-HA stimulated AVP secretion. The stimulatory action of HA on AVP was inhibited by pretreatment with the H1-receptor antagonist mepyramine or the H2-receptor antagonist cimetidine. Twenty-four hours of dehydration elevated the plasma osmolality from 298 +/- 3 to 310 +/- 3 mmol/liter and increased the plasma AVP concentration 4-fold. The hypothalamic content of HA and its metabolite tele-methyl-HA was elevated in response to dehydration, indicating an increased synthesis and release of hypothalamic HA. Dehydration-induced AVP secretion was lowered when neuronal HA synthesis was inhibited by the administration of (S) alpha-fluoromethylhistidine or when the animals were pretreated with the H3-receptor agonist R(alpha)methylhistamine, which inhibits the release and synthesis of HA, the H1-receptor antagonists mepyramine and cetirizine, or the H2-receptor antagonists cimetidine and ranitidine. We conclude that HA, via activation of both H1- and H2-receptors, stimulates AVP release and that HA is a physiological regulator of AVP secretion.

Neuronal Glucoprivation Enhances Hypothalamic Histamine Turnover in Rats

Histamine (HA) turnover in the rat hypothalamus following insufficient energy supply due to glucoprivation was examined after administration of insulin or 2-deoxy-D-glucose (2-DG). HA turnover was assessed by accumulation of tele-methylhistamine (t-MH), a major metabolite of brain HA, following administration of pargyline. Intraperitoneal injection of 1, 2, and 4 U/kg of insulin, which had no influence on steady-state levels of HA and t-MH, increased pargyline-induced accumulation of t-MH. Accumulation of t-MH due to pargyline was inversely related to the concomitant plasma glucose concentration after different doses of insulin. The level of t-MH accumulated by pargyline did not change compared with that of controls, when a euglycemic condition was maintained or insulin at a dose of 6 mU per rat was infused into the third cerebroventricle. Intracerebroventricular infusion of 24 mumol per rat of 2-DG, which had no influence on steady-state levels of HA and t-MH, increased the level of t-MH enhanced by pargyline. The results indicate that an increase in hypothalamic HA turnover in response to glucoprivation may be involved in homeostatic regulation of energy metabolism in the brain.

Dehydration-induced release of vasopressin involves activation of hypothalamic histaminergic neurons

The hypothalamic neurotransmitter histamine (HA) induces arginine vasopressin (AVP) release when administered centrally. We studied and characterized this effect of HA with respect to receptor involvement. In addition, we studied the possible role of hypothalamic histaminergic neurons in the mediation of a physiological stimulus (dehydration) for AVP secretion. Intracerebroventricular administration of HA, the H1-receptor agonists 2(3-bromophenyl)HA and 2-thiazolylethylamine, or the H2-receptor agonists amthamine or 4-methyl-HA stimulated AVP secretion. The stimulatory action of HA on AVP was inhibited by pretreatment with the H1-receptor antagonist mepyramine or the H2-receptor antagonist cimetidine. Twenty-four hours of dehydration elevated the plasma osmolality from 298 +/- 3 to 310 +/- 3 mmol/liter and increased the plasma AVP concentration 4-fold. The hypothalamic content of HA and its metabolite tele-methyl-HA was elevated in response to dehydration, indicating an increased synthesis and release of hypothalamic HA. Dehydration-induced AVP secretion was lowered when neuronal HA synthesis was inhibited by the administration of (S) alpha-fluoromethylhistidine or when the animals were pretreated with the H3-receptor agonist R(alpha)methylhistamine, which inhibits the release and synthesis of HA, the H1-receptor antagonists mepyramine and cetirizine, or the H2-receptor antagonists cimetidine and ranitidine. We conclude that HA, via activation of both H1- and H2-receptors, stimulates AVP release and that HA is a physiological regulator of AVP secretion.

2-deoxy-D-glucose suppresses food intake through activation of hypothalamic histamine in rats.

The aim of this experiment was to demonstrate whether brain histamine contributes to delayed suppression of food intake after administration of 2-deoxy-D-glucose (2-DG). Food intake decreased significantly for 48 h after infusion of 2-DG into the rat third cerebroventricle. This delayed decrease in food intake was abolished by depletion of neuronal histamine by intraperitoneal pretreatment with alpha-fluoromethylhistidine (160 mumol/rat), a suicide inhibitor of a histamine-synthesizing enzyme. Intracerebroventricular infusion of 24 mumol 2-DG accelerated turnover rate of hypothalamic histamine. These results indicate that the delayed feeding suppression by 2-DG is modulated through histaminergic neurons in the hypothalamus. This histaminergic response may be related, at least in part, to homeostatic control of energy metabolism in the brain.

Effect of isolation stress on brain mast cells and brain histamine levels in rats

The effects of the chronic social stress of isolation on changes in brain mast cells (MC), the hypothalamic histamine content and the activity of the hypothalamic-pituitary adrenal (HPA) axis were investigated in rats. Social stress of isolation markedly reduced the total number of brain mast cells, most significantly by 90% in the first day. The extent of MC degranulation, 36-67%, in stressed rats did not significantly differ from that in control animals, 45-58%. Isolation stress substantially, though not significantly, increased the hypothalamic histamine content. The serum corticosterone levels in isolated rats did not significantly differ from the control levels. These results indicate that social stress of isolation considerably diminishes the number of brain MC and suggest that histamine which might be liberated from these cells does not significantly influence the HPA activity.

Effect of crowding on corticosterone responses to central adrenergic stimulation.

The social stress of crowding for 3, 7 and 14 days considerably reduced the increase in serum corticosterone elicited by intracerebroventricular administration of isoprenaline, a beta-adrenergic agonist, on the 3rd and 7th days of crowding. The corticosterone response to clonidine, an alpha 2-adrenergic agonist, was significantly diminished only after 3 days of crowding and this reduction was paralleled by a significant decrease in hypothalamic histamine content. The stimulatory effect of phenylephrine, an alpha 1-adrenergic agonist, was not significantly changed by crowding stress. Social crowding stress caused almost total and persistent reduction in the hypothalamic-pituitary-adrenocortical (HPA) responsiveness to noradrenaline which stimulates the HPA axis via both alpha- and beta-adrenergic receptors.

Hypothalamic neuronal histamine regulates feeding circadian rhythm in rats

To clarify involvement of hypothalamic neuronal histamine in feeding circadian rhythm, we analyzed rat behavioral patterns using chemical probes which affect endogenous histaminergic activity. Sustained infusion of α-fluoromethylhistidine (FMH), a specific suicide inhibitor of a histamine-synthesizing enzyme, into the rat third cerebral ventricle disrupted light-dark cycles of feeding, drinking, and ambulatory behavior. Food and water intake and ambulatory activity during the 12-h light period increased, and those during the 12-h dark period decreased after the infusion. The ratio of the light period to the 24-h total period (L/T ratio) increased in all behavioral parameters. Assessed by 3-h cumulative analysis, amplitudes of circadian rhythmicity decreased in all behavioral parameters, whereas only the acrophase of ambulatory activity shifted forward after FMH infusion. Chlorpheniramine, an H 1-antagonist, selectively increased food intake during the light and decreased it during the dark period. Consequently, the antagonist increased the L/T ratio in food intake, but did not affect the ratio in water intake or ambulatory activity. Famotidine, an H 2-antagonist, did not affect the ratio in any parameter. Thioperamide, an antagonist of auto-inhibitory effects on histamine synthesis and release at presynaptic H 3-receptor sites, decreased food intake during the dark, but did not affect the L/T ratio in any parameter. These findings indicate that neuronal histamine may regulate feeding circadian rhythm through the hypothalamic histamine H 1-receptor in rats.

A physiological role of brain histamine during energy deficiency

Histaminergic activation in the rat hypothalamus was investigated under a deficit in energy supply. Fasting of rats for 24 h increased hypothalamic histamine (HA) content. Intraperitoneal (IP) injection of insulin (2 U/kg) increased pargyline-induced accumulation of tele-methylhistamine ( t-MH) leaving steady-state HA and t-MH levels unaffected, which implies enhancement of HA turnover rate. The insulin infusion induced hypoglycemia both in rats with and without pargyline pretreatment. Infusion of 2-deoxy- D-glucose (2-DG) into the third cerebroventricle also produced an increase in pargyline-induced accumulation of t-MH and no change in steady-state HA and t-MH levels. The 2-DG infusion induced hyperglycemia. Hypothalamic glycogen content decreased after 24 h starvation, but this decrease was prevented by depletion of HA by α-fluoromethylhistidine. Absolute glycogen contents in the cortex were lower than those in the hypothalamus, and were not affected by fasting or depletion of HA. The results indicate that activation of hypothalamic HA in response to glucoprivation may modulate homeostatic control of energy supply in the brain.

Thermoregulation and hypothalamic histamine turnover modulated by interleukin-1β in rats

To clarify the involvement of hypothalamic histamine in thermogenic response provoked by high ambient temperature, or interleukin-1β (IL-1β), changes in rectal temperature and histamine turnover were investigated. Rectal temperature was maintained normally after exposure to high ambient temperature, but elevated by IL-1β. In spite of these different responses of body temperature, hypothalamic histamine turnover was increased in each treatment. The results suggest that hypothalamic histaminergic neurons are activated not only peripherally by high ambient temperature, but also centrally by IL-1β as endogenous pyrogen.

Aminoglucose-induced feeding suppression is regulated by hypothalamic neuronal histamine in rats

Central mechanisms involved in feeding suppression produced by 1-deoxy- d-glucosamine (1-DGlcN) and1-deoxy-N-acetylglucosamine (1- DGlcNAc) are unclear. To clarify the mechanisms, we investigated the role of hypothalamic neuronal histamine (HA) in feeding suppression induced by 1-DGlcN and 1-DGlcNAc in rats. Food intake was suppressed for 3 days after a single infusion of 24 μmol 1-DGlcN into the third cerebroventricle (i.c.v.) Depletion of presynaptic HA due to intraperitoneal infusion (i.p.) of α-fluoromethylhistidine (FMH), a specific inhibitor of the HA synthesizing enzyme histidine decar☐ylase (HDC), abolished feeding suppression completely. Blockade of postsynaptic H 1-receptors by i.p. injection of 26 μmol chlorpheniramine also abolished the suppression. Oral administration of 2.4 mmol 1-DGlcNAc suppressed food intake. However, depletion of neuronal HA due to FMH did not affect the suppression. I.c.v. infusion of 24 μmol 1-DGlcN increased turnover rate of HA at 1 h after the infusion. Hypothalamic HA concentration, but not that of tele-methylhistamine (t-MH), increased at 24 h after i.c.v. infusion of 1-DGlcN, which suggests a correlation between HA concentration and the behavioral response. These results indicate that 1-DGlcN, but not 1-DGlcNAc, modulates feeding suppression through HA neurons in the hypothalamus. Differences in mechanisms of feeding suppression by these aminoglucoses may depend on the principal sites of acton in the brain and/or peripheral organs.

Abnormalities in obese Zuckers: Defective control of histaminergic functions

Histaminergic functions in the hypothalamus of Zucker obese rats were investigated. Blockade of postsynaptic H 1-receptor after infusion of chlorpheniramine into the third cerebroventricle (ICV) failed to affect feeding in obese Zuckers, although feeding was potently elicited in Wistar King A control rats. Presynaptic increase in histamine by an H 3-receptor antagonist, thioperamide, suppressed feeding in Wistar controls, but not in obese Zuckers. Under high ambient temperature, Wistar controls decreased food intake and maintained their rectal temperature normally. However, obese Zuckers and histamine depleted rats due to α-fluoromethyl-histidine (FMH), a specific “suicide” inhibitor of a histamine synthesizing decarboxylase enzyme (HDC), failed to show this decrease in food intake as adaptive behavior. Their rectal temperature concomitantly elevated in response to heated circumstance. ICV infusion of thioperamide increased the blood glucose level in Wistar controls, but not in obese Zuckers. The defect in all these regulatory functions found in obese Zuckers may be derived from an excessive decrease in hypothalamic histamine content due to inactivity of HDC. The histamine-depleted model sufficiently mimicked the abnormalities in obese Zuckers.

Ginsenoside Rg 1 prevents histaminergic modulation of rat adaptive behavior from elevation of ambient temperature

Effects of ginsenoside Rg 1 (Rg 1) on histaminergic modulation of both adaptive behavior and thermoregulation were investigated at high ambient temperature. Continuous infusion of Rg 1 using an osmotic minipump into the rat third cerebroventricle attenuated anorexia induced by elevation of ambient temperature from 21°C to 31°C. Intraperitoneal injection of α-fluoromethylhistidine (FMH), a specific suicide inhibitor of a histamine synthesizing decarboxylase enzyme, also prevented the anorexia induced by elevated temperature. The ratio of water intake to food intake, which showed no change on the first day after elevation of room temperature, was not influenced by treatment of either FMH or Rg 1. Rectal temperature, which was normally maintained at a constant level even after shifting ambient temperature from 21°C to 31°C, elevated after FMH treatment. The Rg 1 infusion, however, maintained rectal temperature normally at 31°C. Hypothalamic histamine content increased in response to elevation of ambient temperature. The Rg 1 infusion maintained constant histamine level against elevation of environmental temperature. Under the heated condition FMH reduced hypothalamic histamine. These findings suggest that Rg 1 may modulate rat adaptive behavior by blockade of temperature-related information into the hypothalamic histamine neurons.

411 Hypothalamic and cortical histamine release in vivo under constant dark condition

411 Hypothalamic and cortical histamine release in vivo under constant dark condition

Responses of anterior pituitary hormones and hypothalamic histamine to blockade of histamine synthesis and to selective activation or inactivation of presynaptic histamine H3 receptors in stressed rats.

The stress-induced release of anterior pituitary hormones and changes in hypothalamic content of histamine (HA) and its metabolite tele-methylHA (t-meHA) were studied in male rats during inhibition of HA synthesis or activation or blockade of HA H3 receptors. Pretreatment with the HA synthesis inhibitor alpha-fluoromethylhistidine (alpha-FMH; 200 micrograms intracerebroventricularly (icv) at -120 min) or the specific H3 receptor agonist R(alpha)methylhistamine (RmHA; 10 mg/kg intraperitoneally (ip) at -180 and -60 min) inhibited by 30-80% the responses of prolactin (PRL), corticotropin (ACTH) and beta-endorphin (beta-END) immunoreactivity to 1, 2.5 or 5 min of restraint stress (p < 0.05-0.01), but had no effect on basal secretion of the hormones. The inhibitory effect of the H3 receptor agonist RmHA (10 mg/kg x 2) on the hormone response to 5 min of restraint stress was prevented by simultaneous ip administration of the H3 receptor antagonist thioperamide. alpha-FMH reduced the hypothalamic content of HA 60% and that of t-meHA 30%, while RmHA had no effect on the HA content. Restraint stress for 5 min did not affect the HA and t-meHA contents, which may be due to the short duration of stress exposure. Pretreatment with the H3 receptor antagonist thioperamide (5 or 10 mg/kg ip at -120 min) had no effect on basal or restraint stress-induced release of PRL, ACTH or beta-END, although the compound increased the hypothalamic content of t-meHA 2-fold.(ABSTRACT TRUNCATED AT 250 WORDS)

1904 Hypothalamic histamine modulates physiological responses induced by circulating interleukin-1β

1904 Hypothalamic histamine modulates physiological responses induced by circulating interleukin-1β

Hypothalamic histamine release, neuroendocrine and cardiovascular responses during tuberomammillary nucleus stimulation in the conscious rat.

Neuronal histamine (HA) in the central nervous system (CNS) has been implicated in control of peripheral cardiovascular and neuroendocrine responses. The tuberomammillary nucleus (TMN) of the posterior hypothalamus contains all CNS HA cell bodies. In these experiments, the TMN was electrically stimulated in conscious rats and HA release in the region of the supraoptic nucleus (SON) was estimated using in vivo microdialysis. In addition, mean arterial blood pressure (MAP), heart rate (HR), and plasma concentrations of norepinephrine (NE) and vasopressin (VP) were measured before, during and following TMN stimulation. Stimulation of the TMN resulted in a significant increase in extracellular HA (110 +/- 29% control) in the region of the SON. MAP, HR and plasma NE concentration were also significantly elevated during TMN stimulation. However, plasma VP concentrations were unchanged. These results show that TMN stimulation in conscious animals releases HA in the region of the SON and is associated with a pressor response, tachycardia, and increased plasma concentration of NE, but not release of VP.