Inhibition Of Histamine Synthesis Research Articles

Increased Sensitivity of Mice Lacking Extrasynaptic δ-Containing GABAA Receptors to Histamine Receptor 3 Antagonists.

Histamine/gamma-aminobutyric acid (GABA) neurons of posterior hypothalamus send wide projections to many brain areas and participate in stabilizing the wake state. Recent research has suggested that GABA released from the histamine/GABA neurons acts on extrasynaptic GABAA receptors and balances the excitatory effect of histamine. In the current study, we show the presence of vesicular GABA transporter mRNA in a majority of quantified hypothalamic histaminergic neurons, which suggest vesicular release of GABA. As histamine/GABA neurons form conventional synapses infrequently, it is possible that GABA released from these neurons diffuses to target areas by volume transmission and acts on extrasynaptic GABA receptors. To investigate this hypothesis, mice lacking extrasynaptic GABAA receptor δ subunit (Gabrd KO) were used. A pharmacological approach was employed to activate histamine/GABA neurons and induce histamine and presumably, GABA, release. Control and Gabrd KO mice were treated with histamine receptor 3 (Hrh3) inverse agonists ciproxifan and pitolisant, which block Hrh3 autoreceptors on histamine/GABA neurons and histamine-dependently promote wakefulness. Low doses of ciproxifan (1 mg/kg) and pitolisant (5 mg/kg) reduced locomotion in Gabrd KO, but not in WT mice. EEG recording showed that Gabrd KO mice were also more sensitive to the wake-promoting effect of ciproxifan (3 mg/kg) than control mice. Low frequency delta waves, associated with NREM sleep, were significantly suppressed in Gabrd KO mice compared with the WT group. Ciproxifan-induced wakefulness was blocked by histamine synthesis inhibitor α-fluoromethylhistidine (αFMH). The findings indicate that both histamine and GABA, released from histamine/GABA neurons, are involved in regulation of brain arousal states and δ-containing subunit GABAA receptors are involved in mediating GABA response.

Inhibitory effects of catechin isolated from Acacia catechu on ovalbumin induced allergic asthma model

Purpose Polyphenols possess anti-allergic activities. Catechin is one of the polyphenols that are abundantly present in the Acacia catechu. In this study, the authors investigated the effect of catechin isolated from A. catechu in an experimental mouse model of ovalbumin (OVA)-induced allergic asthma. Design/methodology/approach Catechin was isolated from A. catechu, and phytochemical analysis was carried out by ultraviolet visible and thin-layer chromatography (TLC), high pressure thin-layer chromatography was used for the determination of an amount of catechin present. In a first set of an experiment, the authors have carried out dose-dependent evaluation of catechin on histamine synthesis in normal rats. In another study, allergic asthma was induced in BALB/c mice by intraperitoneal injection of 50 mg OVA dissolved in 4 mg aluminum hydroxide dissolved in 0.2 ml saline on Days 0 and 14. Catechin was given orally at the dose of 100 mg/kg, once a day from Day 1 to Day 35 and after which various respiratory parameters such as tidal volume, respiratory rate and airflow rate, biochemical parameters such as histamine release from mast cells, bronchoalveolar (BAL) lavage fluid analysis and histopathology of lungs were carried out. Findings Catechin showed significant (p < 0.05) improvement in respiratory parameters such as tidal volume, respiratory rate and airflow rate, as well as biochemical and hematological parameters such as blood histamine, serum bicarbonate and nitric oxide levels as compared to the disease control group. The treatment also showed inhibitory effects on histamine synthesis in rat peritoneal as well as BAL mast cells. Also, a significant (p < 0.05) improvement in lung histopathology was observed with catechin. Originality/value From the present study, the authors can conclude that catechin exhibited potent anti-allergic activity by inhibition of histamine synthesis by inhibition of histidine decarboxylase enzyme. The study suggests that catechin has therapeutic potential for the treatment of allergic inflammatory disease in humans.

Mechanism of the histamine H3 receptor-mediated increase in exploratory locomotor activity and anxiety-like behaviours in mice

Histaminergic neurons are activated by histamine H3 receptor (H3R) antagonists, increasing histamine and other neurotransmitters in the brain. The prototype H3R antagonist thioperamide increases locomotor activity and anxiety-like behaviours; however, the mechanisms underlying these effects have not been fully elucidated. This study aimed to determine the mechanism underlying H3R-mediated behavioural changes using a specific H3R antagonist, JNJ-10181457 (JNJ).First, we examined the effect of JNJ injection to mice on the concentrations of brain monoamines and their metabolites. JNJ exclusively increased Nτ-methylhistamine, the metabolite of brain histamine used as an indicator of histamine release, suggesting that JNJ dominantly stimulates the release of histamine release but not of other monoamines.Next, we examined the mechanism underlying JNJ-induced behavioural changes using open-field tests and elevated zero maze tests. JNJ-induced increase in locomotor activity was inhibited by α-fluoromethyl histidine, an inhibitor of histamine synthesis, supporting that H3R exerted its effect through histamine neurotransmission. The JNJ-induced increase in locomotor activity in wild-type mice was preserved in H1R gene knockout mice but not in histamine H2 receptor (H2R) gene knockout mice. JNJ-induced anxiety-like behaviours were partially reduced by diphenhydramine, an H1R antagonist, and dominantly by zolantidine, an H2R antagonist. These results suggest that H3R blockade induces histamine release, activates H2R and elicits exploratory locomotor activity and anxiety-like behaviours.

Histamine is a modulator of metamorphic competence in Strongylocentrotus purpuratus (Echinodermata: Echinoidea).

BackgroundA metamorphic life-history is present in the majority of animal phyla. This developmental mode is particularly prominent among marine invertebrates with a bentho-planktonic life cycle, where a pelagic larval form transforms into a benthic adult. Metamorphic competence (the stage at which a larva is capable to undergo the metamorphic transformation and settlement) is an important adaptation both ecologically and physiologically. The competence period maintains the larval state until suitable settlement sites are encountered, at which point the larvae settle in response to settlement cues. The mechanistic basis for metamorphosis (the morphogenetic transition from a larva to a juvenile including settlement), i.e. the molecular and cellular processes underlying metamorphosis in marine invertebrate species, is poorly understood. Histamine (HA), a neurotransmitter used for various physiological and developmental functions among animals, has a critical role in sea urchin fertilization and in the induction of metamorphosis. Here we test the premise that HA functions as a developmental modulator of metamorphic competence in the sea urchin Strongylocentrotus purpuratus.ResultsOur results provide strong evidence that HA leads to the acquisition of metamorphic competence in S. purpuratus larvae. Pharmacological analysis of several HA receptor antagonists and an inhibitor of HA synthesis indicates a function of HA in metamorphic competence as well as programmed cell death (PCD) during arm retraction. Furthermore we identified an extensive network of histaminergic neurons in pre-metamorphic and metamorphically competent larvae. Analysis of this network throughout larval development indicates that the maturation of specific neuronal clusters correlates with the acquisition of metamorphic competence. Moreover, histamine receptor antagonist treatment leads to the induction of caspase mediated apoptosis in competent larvae.ConclusionsWe conclude that HA is a modulator of metamorphic competence in S. purpuratus development and hypothesize that HA may have played an important role in the evolution of settlement strategies in echinoids. Our findings provide novel insights into the evolution of HA signalling and its function in one of the most important and widespread life history transitions in the animal kingdom - metamorphosis.

Pyeongwee-San extract (KMP6): a new anti-allergic effect

The prevalence of allergic diseases is increasing due to rapid industrialization and changes in lifestyle. Pyeongwee-San (KMP6) is a traditional Korean medicine that has been used as a basic prescription for digestive disorders. This study investigated the efficacy of KMP6 and its component hesperidin on experimental allergic models. The anti-allergic effect of KMP6 was studied against a compound 48/80-induced systemic anaphylactic reaction and the ear swelling response. In addition, a human mast cell line (HMC-1) was used to analyze the activity of histidine decarboxylase. Passive cutaneous anaphylaxis (PCA) from immunoglobulin E (IgE) was used. KMP6 and hesperidin inhibited the compound 48/80-induced systemic anaphylactic reaction and the ear swelling response as well as histamine release, intracellular calcium levels and tryptase release from rat peritoneal mast cells. KMP6 inhibited histidine decarboxylase activity in stimulated HMC-1 cells and macrophages. In addition, KMP6 inhibited the PCA reaction induced by IgE as well as the levels of IgE, interleukin (IL)-4, IL-5, IL-6 and IL-13 in serum from mice. These results suggest that KMP6 may exert an anti-allergic effect through not only the inhibition of mast cell degranulation but also the inhibition of histamine synthesis.

Inhibition of histidine decarboxylase ablates the autocrine tumorigenic effects of histamine in human cholangiocarcinoma

BackgroundIn several tumours the endogenous activity of histidine decarboxylase (HDC), the enzyme stimulating histamine synthesis, sustains the autocrine trophic effect of histamine on cancer progression. Cholangiocarcinoma is a biliary cancer...

Alpha-fluoromethylhistidine, a histamine synthesis inhibitor, inhibits orexin-induced wakefulness in rats

Orexins A and B are involved in the regulation of feeding and arousal state. Previously, we reported that third intracerebroventricular (icv) infusion of both orexins A and B induced a significant arousal effect in rats. We determined the effects of intraperitoneal (i.p.) injection of alpha-fluoromethylhistidine (α-FMH), a histamine synthesis inhibitor, on orexin-induced wakefulness in freely behaving rats. Male Sprague–Dawley rats were chronically implanted with cortical electroencephalogram (EEG) and neck electromyogram (EMG) electrodes, and a cannula for icv infusion. EEG and EMG were monitored for three consecutive days during continuous icv saline infusion at a rate of 10 μl/h. For a 5-h diurnal period, orexin-B (10 nmol/50 μl saline) replaced the icv infusion of saline. α-FMH (100 mg/kg, i.p.) was administered 6 h before icv infusion of orexin-B. Orexin-B at a dose of 10 nmol/h markedly increased the amount of wakefulness by 99.4% ( p < 0.05) over the baseline value, whereas α-FMH decreased orexin-B-induced wakefulness by 48.8%. Orexin-B-induced suppression of non-REM sleep was reversed by α-FMH treatment. Pretreatment with α-FMH, significantly inhibited orexin-B-induced wakefulness in rats. The findings of this study therefore suggest that arousal-state regulation by orexin neurons is possibly mediated via the histaminergic system in the tuberomammilary nucleus.

Therapeutic potential of histamine H3 receptor agonist for the treatment of obesity and diabetes mellitus.

Histamine H3 receptors (H3Rs) are located on the presynaptic membranes and cell soma of histamine neurons, where they negatively regulate the synthesis and release of histamine. In addition, H3Rs are also located on nonhistaminergic neurons, acting as heteroreceptors to regulate the releases of other amines such as dopamine, serotonin, and norepinephrine. The present study investigated the effects of H3R ligands on appetite and body-weight regulation by using WT and H3R-deficient mice (H3RKO), because brain histamine plays a pivotal role in energy homeostasis. The results showed that thioperamide, an H3R inverse agonist, increases, whereas imetit, an H3R agonist, decreases appetite and body weight in diet-induced obese (DiO) WT mice. Moreover, in DiO WT mice, but not in DiO H3RKO mice, imetit reduced fat mass, plasma concentrations of leptin and insulin, and hepatic triglyceride content. The anorexigenic effects of imetit were associated with a reduction in histamine release, but a comparable reduction in histamine release with alpha-fluoromethylhistidine, an inhibitor of histamine synthesis, increased appetite. Moreover, the anorexigenic effects of imetit were independent of the melanocortin system, because imetit comparably reduced appetite in melanocortin 3 and 4 receptor-deficient mice. The results provide roles of H3Rs in energy homeostasis and suggest a therapeutic potential for H3R agonists in the treatment of obesity and diabetes mellitus.

Histaminergic Neurons Protect the Developing Hippocampus from Kainic Acid-Induced Neuronal Damage in an Organotypic Coculture System

The central histaminergic neuron system inhibits epileptic seizures, which is suggested to occur mainly through histamine 1 (H1) and histamine 3 (H3) receptors. However, the importance of histaminergic neurons in seizure-induced cell damage is poorly known. In this study, we used an organotypic coculture system and confocal microscopy to examine whether histaminergic neurons, which were verified by immunohistochemistry, have any protective effect on kainic acid (KA)-induced neuronal damage in the developing hippocampus. Fluoro-Jade B, a specific marker for degenerating neurons, indicated that, after the 12 h KA (5 microM) treatment, neuronal damage was significantly attenuated in the hippocampus cultured together with the posterior hypothalamic slice containing histaminergic neurons [HI plus HY (POST)] when compared with the hippocampus cultured alone (HI) or with the anterior hypothalamus devoid of histaminergic neurons. Moreover, alpha-fluoromethylhistidine, an inhibitor of histamine synthesis, eliminated the neuroprotective effect in KA-treated HI plus HY (POST), and extracellularly applied histamine (1 nM to 100 microM) significantly attenuated neuronal damage only at 1 nM concentration in HI. After the 6 h KA treatment, spontaneous electrical activity registered in the CA1 subregion contained significantly less burst activity in HI plus HY (POST) than in HI. Finally, in KA-treated slices, the H3 receptor antagonist thioperamide enhanced the neuroprotective effect of histaminergic neurons, whereas the H1 receptor antagonists triprolidine and mepyramine dose-dependently decreased the neuroprotection in HI plus HY (POST). Our results suggest that histaminergic neurons protect the developing hippocampus from KA-induced neuronal damage, with regulation of neuronal survival being at least partly mediated through H1 and H3 receptors.

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.

Modifying effects of histamine on circadian rhythms and neuronal excitability

Histaminergic activity shows a clear circadian rhythm: high levels during the active period (in rodents at night, in monkeys and humans during the day), and low levels during the sleep period. Histamine appears to be necessary for the maintenance of the circadian rhythmicity of the adrenocortical hormone release, locomotor activity and food intake, and the sleep–wakefulness cycle. In addition, a role for histaminergic neurons in the light entrainment is implicated. In phase shift studies, histamine given centrally seems to entrain the activity rhythm in the same way as light impulses and inhibition of histamine synthesis seems to block the entrainment by light. Importantly, histamine participates in the control of arousal and may be implicated in the sleep disturbances in hepatic encephalopathy. Furthermore, evidence suggests a role for histamine in overall neuronal excitability and seizure susceptibility both in animals and humans. Thus, we conclude that histamine may exert modifying effects on circadian rhythmicity and neuronal excitability.

Inhibition of effects of endogenously synthesized histamine disturbs in vitro human dendritic cell differentiation

Histamine, a principal mediator in various physiological and pathological cell functions is synthesized from l-histidine exclusively by histidine decarboxylase, an enzyme, which is expressed in many tissues of mammalian organism. Histamine plays a role in various cellular functions, including cell differentiation. The aim of this study was to determine the presence and to characterize the role of the endogenously produced histamine during in vitro dendritic cell (DC) differentiation induced by interleukin-4 (IL-4) and granulocyte-monocyte colony stimulating factor (GM-CSF). The changes in intracellular histamine content, biosynthesis and gene expression of histidine decarboxylase were investigated during this process. One also studied how histamine receptor antagonists and a histamine synthesis blocker influence the expression of differentiation antigens on the DC during in vitro maturation. During in vitro differentiation parallel culture incubations were performed by adding H1 receptor antagonist triprolidine, H2 receptor antagonist tiotidine, the tamoxifene derivate DPPE which blocks the intracellular binding of histamine, and an irreversible blocker of histidine decarboxylase, α-fluoromethyl histamine (α-FMH). The results show simultaneous increase in both histidine decarboxylase level and histamine content during differentiation of elutriated monocytes toward DC. Both blockade of de novo histamine production (by α-FMH) and inhibition of histamine binding (by H1 and H2 receptor antagonists, triprolidine and tiotidine, respectively) markedly decreased CD40 expression and that of CD45 from the 3rd day of treatment. DPPE by disturbing intracellular interaction of histamine with cytochrome P-450 moieties was able to decrease the expression of CD45, CD86, HLA-DR, CD33, CD40 and CD11c. Based on the data it is suggested that endogenous histamine is actively synthesized during cytokine-induced in vitro DC differentiation. The functional relevance and autocrine and paracrine action of endogenously produced histamine is supported by the data showing that inhibition of histamine synthesis by HDC, blocking of histamine binding by both ‘extracellular’ histamine receptors (by specific antagonists, triprolidine and tiotidine) and ‘intracellular’ antagonists (DPPE) disturb the differentiation of DC. This conclusion is supported by the fact, that by the inhibition of histamine acting in an autocrine/paracrine way, the expression pattern of differentiation markers on DC is markedly changed.

Effects of Histamine on Circadian Rhythms and Hibernation

Histamine appears to play a role in regulation of sleep and arousal as well as in synchronizing endogenous circadian rhythms with exogenous photic cues. Direct application of histamine to the suprachiasmatic nucleus (SCN), the site of the mammalian circadian pacemaker, phase shifts the circadian rhythm in neural activity. Intraventricular injections of histamine also phase shift circadian rhythms as do micro-injections directed towards the SCN. The magnitude and direction of the phase shifting effects of histamine depend on circadian phase in a manner similar to light. Depletion of brain histamine levels by inhibition of histamine synthesis reduces phase shifts to light. Histamine appears to influence phase shifts to light via a direct modulation of NMDA receptors in the SCN. Increased histamine levels and turnover observed in hibernating animals render it possible that histamine is a key regulator of hibernation. Thus histamine participates in an important link between sleep, circadian rhythms, and hibernation.

Histamine and prostaglandin interaction in the central regulation of ACTH secretion.

Since prostaglandins (PGs) and histamine (HA) seem to be involved in the activation of the hypothalamic-pituitary-adrenal axis following immunochallenges with lipopolysaccharide (LPS) endotoxin and cytokines, we investigated whether the histaminergic and eicosanoid systems in the male rat brain interact in their regulation of ACTH secretion. The PG synthesis inhibitor indomethacin (10 mg/kg i.p.) attenuated the ACTH response to LPS (10 micrograms/kg i.p.) and HA (30 micrograms i.c.v.). Infusion of PGE1, PGE2 or PGF2 alpha (1 and/or 5 micrograms infused intracerebroventricularly) stimulated ACTH secretion. The ACTH response to PGE1 was inhibited by the HA synthesis inhibitor alpha-fluoromethyl-histidine and the H1 receptor antagonist mepyramine (MEP) but not the H2 receptor antagonist cimetidine (CIM). Neither MEP nor CIM affected the ACTH response to PGE2. MEP and CIM attenuated the ACTH response induced by PGF2 alpha. The findings indicate that HA and some PGs in the brain interact in their stimulatory regulation of ACTH secretion. Such an interaction may also be involved in their mediation of the ACTH response to immunochallenges.

Influence of histamine receptor agonists and antagonists on ultradian rhythm of EEG in the posterior hypothalamus of the rat

The delta and theta frequency bands of the electroencephalogram (EEG) in the posterior hypothalamic area (PH) of rats vary according to an ultradian rhythm with a frequency of approximately 1 cycle/100 min. The influence of histamine-related drugs on the ultradian hypothalamic EEG rhythm was now studied in urethane anaesthetized rats. Injected into the lateral ventricle, metoprine (inhibitor of histamine catabolism) and αuoromethylhistidine (inhibitor of histamine synthesis) did not alter the duration of the rhythmic changes. The H 1 receptor agonist 2-(2-aminoethyl)-thiazole was ineffective, while mepyramine (H 1 receptor antagonist) prolonged the cycle duration of delta and theta frequency bands. Stimulation of H 2 and H 3 receptors by amthamine and immepip, respectively, also prolonged the cycle duration of these frequency bands, while the H 2 antagonist famotidine and the H 3 antagonist thioperamide exerted the opposite effect. Our results indicate that the ultradian EEG rhythm in the PH is susceptible to regulatory influences mediated by the histaminergic system of the brain.

Inhibition of histamine synthesis by glycyrrhetinic acid in mast cells cocultured with Swiss 3T3 fibroblasts.

The effect of glycyrrhetinic acid (18-O-beta-glycyrrhetinic acid, GA) on histamine metabolism was investigated in cultured mast cells (CMCs) cocultured with Swiss 3T3 fibroblasts. GA strongly inhibited histamine synthesis in the cocultured CMCs. Since 50 microM GA inhibited about 80% of histidine decarboxylase (HDC) activity, the inhibitory activity of GA for histamine synthesis was considered to be derived from the inhibition of HDC activity. The number of berberine-sulfate-positive cells also decreased in the presence of GA, which indicated that maturation of CMCs was inhibited by GA. Furthermore, we examined the effect of GA on the mRNA expression of novel protein kinase C delta (nPKC delta), a major isoform of CMCs, by northern blot analysis. The expression of nPKC delta mRNA in the presence of GA was significantly lower than in the absence of GA. These results suggest the possibility that the inhibition of histamine synthesis by GA is regulated by nPKC delta.

Involvement of Histamine in Suckling-Induced Release of Oxytocin, Prolactin and Adrenocorticotropin in Lactating Rats

We have previously shown that histaminergic neurons participate in mediation of the prolactin (PRL), adrenocorticotropin (ACTH) and oxytocin responses to physiological stimuli such as stress and dehydration. Since suckling is a potent stimulus for the secretion of these three hormones, we investigated the mediating role of neuronal histamine in suckling-induced release of oxytocin, PRL and ACTH in conscious lactating rats. The animals were pretreated with the histamine synthesis inhibitor alpha-fluoromethylhistidine, the H1 receptor antagonist mepyramine, the H2 receptor antagonist cimetidine or the H3 receptor agonist R (alpha) methylhistamine, which by binding to H3 autoreceptors inhibits histamine release and synthesis. After the lactating rats were separated from their pups for 240 min, the pups were returned for a suckling period of 20 min. Thereafter the mothers were sacrificed by decapitation and trunk blood was collected for determination of hormones. Lactating rats not exposed to suckling served as controls. Suckling increased oxytocin 2-fold, PRL 50-fold and ACTH 5-fold. Blockade of histamine synthesis by alpha-fluoromethylhistidine or histamine release by R(alpha)methylhistamine reduced the suckling-induced secretion of the three hormones significantly. Blockade of postsynaptic H1 receptors by mepyramine inhibited the hormone responses to suckling, while the blockade of postsynaptic H2 receptors by cimetidine decreased the suckling-induced oxytocin and PRL release but did not affect the ACTH release. None of the compounds affected oxytocin, PRL or ACTH secretion in lactating mothers not exposed to suckling. In addition, suckling significantly increased the mRNA of the histamine synthesizing enzyme histidine decarboxylase in the ventrolateral tuberomammillary nucleus by 1.5-fold, indicating that the stimulus of suckling enhances the neuronal histamine synthesis. We conclude that suckling increases neuronal histamine synthesis and that histaminergic neurons by activation of postsynaptic H1 and H2 receptors are involved in the hypothalamic mediation of oxytocin, PRL and ACTH responses to suckling. These findings further substantiate a role of neuronal histamine in the neuroendocrine regulation of pituitary hormones in response to physiological stimuli.

Histamine synthesis inhibition reduces light-induced phase shifts of circadian rhythms

Circadian rhythms are generated by the hypothalamic suprachiasmatic nuclei, a site of dense histaminergic innervation. Histamine can phase shift circadian rhythms in a manner similar to light. In this experiment, we administered α-fluoromethylhistidine (FMH), an inhibitor of histamine synthesis, prior to a light pulse in hamsters housed under constant darkness. Photic phase shifts in wheel-running rhythms were significantly attenuated by FMH pretreatment. These results suggest that histamine may modulate photic input to the circadian clock.

Dehydration stimulates hypothalamic gene expression of histamine synthesis enzyme: importance for neuroendocrine regulation of vasopressin and oxytocin secretion.

Dehydration associated with hyperosmolality and decreased extracellular volume stimulates arginine vasopressin (AVP) and oxytocin (OT) secretion from magnocellular neurons of the hypothalamus. The effects of hyperosmolality and decreased extracellular volume on the magnocellular neurons are mainly indirect and seem to be mediated centrally via several neurotransmitters and neuropeptides. Because histamine (HA), which serves as a central neurotransmitter, releases AVP and OT from the neurohypophysis when administered centrally, we investigated the possible role of HA in dehydration-induced AVP and OT secretion. To do this, we studied 1) the effect of dehydration on messenger RNA (mRNA) expression of the HA synthesis enzyme, histidine decarboxylase (HDC), in the tuberomammillary nucleus of the hypothalamus; and 2) the effect of HA synthesis inhibition during dehydration on AVP and OT mRNA expression in the supraoptic nucleus of the hypothalamus as well as on plasma AVP and OT levels. Forty-eight hours of dehydration increased the mRNA level of HDC in the tuberomammillary nuclei, whereas 24 h of dehydration had no effect. Pretreatment with the HA synthesis inhibitor alpha-fluoromethylhistidine (alpha FMH) increased the expression of HDC mRNA in 24-h dehydrated rats, but had no effect in euhydrated rats. In rats dehydrated for 48 h, the already increased level of HDC mRNA was not increased further by alpha FMH. Twenty-four and 48 h of dehydration increased AVP and OT mRNA levels in the supraoptic nucleus. This effect was inhibited by alpha FMH pretreatment. Dehydration increased the plasma levels of AVP and OT to an extent which depended on the duration of dehydration. Pretreatment with alpha FMH inhibited the hormone responses to 24 h of dehydration, but did not affect the responses to 48 h of dehydration. Twenty-four and 48 h of dehydration had no significant effect on the contents of AVP and OT in the neurohypophysis, whereas pretreatment with alpha FMH combined with 48 h of dehydration led to depletion of AVP stores in the neurohypophysis. Based on the present findings, we conclude that hypothalamic histaminergic neurons are involved in the regulation of dehydration-induced stimulation of magnocellular AVP and OT neurons.

Dehydration stimulates hypothalamic gene expression of histamine synthesis enzyme: importance for neuroendocrine regulation of vasopressin and oxytocin secretion

Dehydration associated with hyperosmolality and decreased extracellular volume stimulates arginine vasopressin (AVP) and oxytocin (OT) secretion from magnocellular neurons of the hypothalamus. The effects of hyperosmolality and decreased extracellular volume on the magnocellular neurons are mainly indirect and seem to be mediated centrally via several neurotransmitters and neuropeptides. Because histamine (HA), which serves as a central neurotransmitter, releases AVP and OT from the neurohypophysis when administered centrally, we investigated the possible role of HA in dehydration-induced AVP and OT secretion. To do this, we studied 1) the effect of dehydration on messenger RNA (mRNA) expression of the HA synthesis enzyme, histidine decarboxylase (HDC), in the tuberomammillary nucleus of the hypothalamus; and 2) the effect of HA synthesis inhibition during dehydration on AVP and OT mRNA expression in the supraoptic nucleus of the hypothalamus as well as on plasma AVP and OT levels. Forty-eight hours of dehydration increased the mRNA level of HDC in the tuberomammillary nuclei, whereas 24 h of dehydration had no effect. Pretreatment with the HA synthesis inhibitor alpha-fluoromethylhistidine (alpha FMH) increased the expression of HDC mRNA in 24-h dehydrated rats, but had no effect in euhydrated rats. In rats dehydrated for 48 h, the already increased level of HDC mRNA was not increased further by alpha FMH. Twenty-four and 48 h of dehydration increased AVP and OT mRNA levels in the supraoptic nucleus. This effect was inhibited by alpha FMH pretreatment. Dehydration increased the plasma levels of AVP and OT to an extent which depended on the duration of dehydration. Pretreatment with alpha FMH inhibited the hormone responses to 24 h of dehydration, but did not affect the responses to 48 h of dehydration. Twenty-four and 48 h of dehydration had no significant effect on the contents of AVP and OT in the neurohypophysis, whereas pretreatment with alpha FMH combined with 48 h of dehydration led to depletion of AVP stores in the neurohypophysis. Based on the present findings, we conclude that hypothalamic histaminergic neurons are involved in the regulation of dehydration-induced stimulation of magnocellular AVP and OT neurons.