The intracerebroventricularly administered mast cells degranulator compound 48/80 increases the pituitary-adrenocortical activity in rats

The effect of brain mast cells degranulation by compound 48/80 on the pituitary-adrenocortical activity, measured indirectly through corticosterone secretion, and the involvement of a histaminergic mechanism in that stimulation was investigated in conscious rats. All the drugs were given intracerebroventricularly (icv), histamine antagonists 15 min prior to compound 48/80. Compound 48/80 induced a significant dose- and time-related increase in the serum corticosterone levels. That increase, measured 1 h after adminstration of compound 48/80, was moderately diminished by icv pretreatment of rats with mepyramine and cimetidine, histamine H₁- and H₂-receptor antagonists. Three hours after administration of compound 48/80 mast cells of the thalamus and the hypothalamus were completely degranulated. At the same time the thalamus and the whole brain histamine levels were substantially higher than in the saline-treated control rats.The above results suggest that histamine liberated from the brain mast cells and central histamine receptors play a moderate role in increasing the pituitary-adrenocortical activity by compound 48/80.The study was supported by the Polish Academy of Sciences, grant No. 06.03.     

Autoinhibition of histamine synthesis mediated by presynaptic H3-receptors

The regulation of histamine synthesis was studied on rat brain slices or synaptosomes labeled with L-[3H]histidine. Depolarization by increased extracellular K+ concentration enhanced by about twofold the [3H]histamine formation in slices of cerebral cortex. This stimulation was also observed, although to a lesser extent, in synaptosomes from cerebral cortex and slices from the posterior hypothalamus where most histaminergic cell-bodies are located, suggesting that it may occur in nerve endings as well as in perikarya. In the presence of exogenous histamine in increasing concentrations the K+-induced stimulation was progressively reduced by up to 60-70%. The effect of exogenous histamine appears to be receptor-mediated as shown by its saturable character, high pharmacological specificity and competitive reversal by histamine antagonists. The EC50 value of histamine for synthesis reduction (0.34 +/- 0.03 microM) was similar to its EC50 value for release inhibition known to be mediated by H3-receptors. In addition, whereas mepyramine and tiotidine, two potent antagonists at H1- and H2-receptors, respectively, were poorly effective, the H3-receptor antagonists burimamide and impromidine reversed the histamine effect in an apparently competitive manner. These effects were observed in slices of cerebral cortex or posterior hypothalamus as well as in cortical synaptosomes. Furthermore, even in the absence of added histamine, H3-receptor antagonists enhanced the depolarization-induced stimulation of [3H]histamine synthesis, indicating a participation of released endogenous histamine in the synthesis control process. The potencies of H3-receptor antagonists were similar to those of these agents at presynaptic autoreceptors controlling [3H]histamine release. It is concluded that H3-receptors control not only release but also synthesis of histamine at the level of nerve endings and also, presumably, of perikarya. A relationship between the two regulatory processes, possibly via intracellular calcium, seems likely but remains to be investigated at the molecular level.     

Release of acetylcholine in the ventral striatum is influenced by histamine receptors

To investigate whether histamine receptor ligands influence thein vivo-release of acetylcholine in the ventral striatum, this brain region was superfused with histamine receptor agonists or antagonists through a push-pull cannula and drug effects on the release of acetylcholine were investigated.

Histamine, the H₁ receptor agonist 2-thiazolyl-ethylamine and the H₃ receptor antagonist thioperamide enhanced acetylcholine release, while the H₃ receptor agonist (R)-α-methylhistamine was ineffective. The results indicate that H₁ receptors and H₃ receptors modulate acetylcholine release.

The thioperamide-induced increase of acetylcholine release might be exerted via H₃-receptors located on cholinergic terminals. Alternatively, thioperamide might enhance acetylcholine release by incresing endogenous histamine release via H₃ autoreceptors.

It is concluded that, via stimulation of striatal H₁- and H₃ receptors, histaminergic neurons are involved in the regulation of cholinergic neuronal activity in the ventral striatum.

     

Hypothalamic histamine, growth rate, plasma prolactin and growth hormone levels in rats with long-term portacaval anastomosis

OBJECTIVE AND DESIGN: Histamine can modulate feeding behaviour and hormone release; therefore we examined the hypothalamic histamine system, the growth pattern and the serum levels of prolactin and growth hormone in rats with portacaval anastomosis (PCA). Material: The growth rate of 30 PCA- and 30 sham-operated male Han:Wistar rats was monitored for 6 months. Thirteen sham and 9 PCA rats were used for biochemical studies. METHODS: Histamine was assayed by HPLC, tele-methylhistamine by GC-MS, prolactin and growth hormone by RIA. Student's t-test was used to compare the groups. RESULTS: Six months after surgery, the PCA rats exhibited marked growth retardation (weight gain of 20 g vs. 140 g for the sham rats; p < 0.001), increased plasma levels of prolactin (9.7 +/- 2.4 vs. 3.6 +/- 0.6; p<0.01) and unaltered growth hormone levels (6.2 +/- 0.5 vs. 8.1 +/- 1.0). A six-fold elevation of histamine concentration (29.5 +/- 3.9 vs. 4.8 +/- 0.4; p<0.001) and a two-fold increase of tele-methylhistamine levels (1.8 +/- 0.1 vs. 0.8 +/- 0.02; p<0.001) were found in hypothalamus. CONCLUSION: We suggest that increased histaminergic activity in the hypothalamus may be involved in the development of growth retardation and in the enhanced basal secretion of prolactin in male rats with long-term PCA.     

A histaminergic H2-receptor antagonist, ranitidine, blocks the suppressive vasopressin response to fear-related emotional stress in the rat.

The effects of intracerebroventricularly (i.c.v.) administered histaminergic receptor antagonists on plasma levels of vasopressin, oxytocin, prolactin and adrenocorticotrophic hormone (ACTH) after fear-related emotional stress were investigated in the male rat. Pyrilamine, a histaminergic H1-receptor antagonist did not significantly alter the suppressive vasopressin or the facilitative prolactin response to nonassociatively applied emotional stress. On the other hand, i.c.v. administered ranitidine, a histaminergic H2-receptor antagonist, blocked these responses to stress. Pyrilamine again did not significantly change the suppressive vasopressin response to the associatively applied emotional stress. However, the drug attenuated the prolactin response slightly but significantly. Ranitidine blocked the suppressive vasopressin and the facilitative prolactin responses to the associatively applied emotional stress, but the drug did not change the facilitative oxytocin or ACTH response to the stress. Suppression of motor activity during the associatively applied emotional stress was not significantly changed by either of these antagonists. These results suggest that histaminergic H2 receptors are selectively involved in the neural pathways which mediate the suppressive vasopressin and the facilitative prolactin responses to fear-related emotional stress.     

Involvement of the brain histaminergic system in addiction and addiction-related behaviors: A comprehensive review with emphasis on the potential therapeutic use of histaminergic compounds in drug dependence

Neurons that produce histamine are exclusively located in the tuberomamillary nucleus of the posterior hypothalamus and send widespread projections to almost all brain areas. Neuronal histamine is involved in many physiological and behavioral functions such as arousal, feeding behavior and learning. Although conflicting data have been published, several studies have also demonstrated a role of histamine in the psychomotor and rewarding effects of addictive drugs. Pharmacological and brain lesion experiments initially led to the proposition that the histaminergic system exerts an inhibitory influence on drug reward processes, opposed to that of the dopaminergic system. The purpose of this review is to summarize the relevant literature on this topic and to discuss whether the inhibitory function of histamine on drug reward is supported by current evidence from published results. Research conducted during the past decade demonstrated that the ability of many antihistaminic drugs to potentiate addiction-related behaviors essentially results from non-specific effects and does not constitute a valid argument in support of an inhibitory function of histamine on reward processes. The reviewed findings also indicate that histamine can either stimulate or inhibit the dopamine mesolimbic system through distinct neuronal mechanisms involving different histamine receptors. Finally, the hypothesis that the histaminergic system plays an inhibitory role on drug reward appears to be essentially supported by place conditioning studies that focused on morphine reward. The present review suggests that the development of drugs capable of activating the histaminergic system may offer promising therapeutic tools for the treatment of opioid dependence.     

Selective expression of histamine receptors in rat mesencephalic trigeminal neurons

The perikarya of sensory neurons of the mesencephalic trigeminal nucleus (MTN) receive dense histaminergic hypothalamic innervation. In this study, we examine the yet unknown expression and localization of histamine receptors in the rat MTN using immunohistochemistry with subtype-specific antibodies. Same as the masticatory muscle spindle somata H1 receptors were located along the entire MTN, whereas H3 receptors were detected in the caudal pontine part of the nucleus, which receives input from periodontal afferents. Most of the immunostained cell bodies were surrounded by histidine decarboxylase-, histamine- or vesicular monoamine transporter 2-containing pericellular varicose fibers and terminals in a basket-like manner. Our results suggest that rat MTN neurons are directly influenced by histaminergic descending projections from the hypothalamus. It can be inferred that processing of proprioceptive information at the level of the MTN is controlled via histamine H1 and H3 receptors through different postsynaptic mechanisms.     

Antagonistic analogs of luteinizing hormone-releasing hormone are mast cell secretagogues

The histamine-releasing activity of luteinizing hormone-releasing hormone (LHRH) antagonistic analogs has been documented. Antagonists of LHRH elicited in vitro histamine release from mast cells obtained from previously unexposed rats. Intradermal injection of the antagonists caused increased local skin permeability. Anaphylactoid reactions followed subcutaneous injection of the antagonists and in some cases these edematous reactions were accompanied by increased serum histamine levels. These studies show that these small peptides can cause mast cell degranulation and suggest that the neuropeptide, LHRH, may have modulating effects on the immune system.     

Increased neuronal histamine in thiamine-deficient rats

Previous studies have indicated that thiamine deficiency is associated with clearly elevated histamine concentrations in the rat hypothalamus, whereas other brain regions contain normal amounts of the amine. The purpose of this study was to find out if the increased hypothalamic histamine concentrations are due to increased numbers of mast cells or changes in neuronal histamine stores.Thiamine-deficiency was induced by daily injections of pyrithiamine until the animals lost the righting reflex. Control animals were pair-fed with either thiamine-deficient or normal thiamine-supplemented food. A significant increase in histamine concentration was observed in the hypothalamus and pons-medulla of the pyrithiamine-treated rats, but not in the cerebellum, thalamus, cerebral cortex or pituitary gland. Immunohistochemically, no histamine-containing mast cells were found in the hypothalami of the pyrithiamine-treated rats or control animals. The histaminergic tuberomammillary neurons were very intensely immunofluorescent, and the density of histamine-immunoreactive nerve fibers in the hypothalamus was also increased in the pyrithiamine-treated animals.     

Pathophysiological significance of the distribution of histamine receptor sub-types: a proposed dual role for histamine in inflammation and Type I hypersensitivity reactions

The pathophysiological significance of histaminergic receptors located on the membranes of immunocompetent cells is reviewed. H₂-receptor agonists decrease the immunological histamine release from isolated serosal mast cells and from isolated hearts taken from actively sensitised guinea-pigs. Histamine and H₂-receptor agonists inhibit the generation of superoxide anion from human neutrophils activated by FMLP and by substance P.These observations lend further support to the hypothesis of an immunodepression exerted by the activation of H₂-receptors, which can be converted to immunostimulation by treatment with H₂-receptor antagonists.     

Prostaglandin E potentiates the immunologically stimulated histamine release from human peripheral blood-derived mast cells through EP1/EP3 receptors

BACKGROUND: Mast cells cultured from human peripheral blood have been widely used to study human mast cell function. Prostanoids are the important regulators of mast cell activity, however, there were no reports about the class of prostanoid receptors expressed on such cultured cells. AIMS: The present study was to characterize pharmacologically the prostanoid receptors by investigating the effects of prostanoid receptor agonists on the immunoglobulin E (IgE)-mediated histamine release from the cultured mast cells. METHODS: Mast cells cultured from human progenitor cells in peripheral blood were sensitized with human myeloma IgE, and then challenged with anti-human IgE following pretreatment with diverse prostanoid receptor agonists. The histamine content in supernatants and cell pellets were measured by histamine auto-analyzer. RESULTS: Of the prostanoid receptor agonists tested, the prostaglandin E2 (PGE2) receptor (EP receptor) agonist PGE2 (10(-7) to 10(-11) M) produced concentration-related potentiation of IgE-mediated histamine release from the cultured mast cells. Sulprostone, an EP1/EP3 agonist, SC-46275, a selective EP3 agonist, and 11-deoxy-PGE1, a selective EP2/EP3/EP4 agonist also caused a significant increase in histamine release induced by anti-IgE. BW245C, fluprostone, cicaprost and U46619 for the prostaglandin D2, F2alpha, I2, and thromboxane A2 receptors respectively, and the EP2/EP4 receptor agonist butaprost had little effect on anti-IgE stimulated histamine release from mast cells. CONCLUSIONS: The present results suggest that PGE2 potentiates the IgE-mediated histamine release from the cultured mast cell via EP3 and/or EP1 receptors.     

Histamine improves rat rota-rod and balance beam performances through H(2) receptors in the cerebellar interpositus nucleus

Previous studies have revealed a direct histaminergic projection from the tuberomamillary nucleus of hypothalamus to the cerebellum and a postsynaptic excitatory effect of histamine on the cerebellar interpositus nucleus neurons via histamine H(2) receptors in vitro, indicating that the histaminergic afferent inputs of cerebellar nuclei may be involved in the cerebellar function of motor control. To test this hypothesis, in this study histaminergic agents were bilaterally microinjected into the cerebellar interpositus nucleus of intact adult male rats, and their effects on motor balance and coordination of the animals performing accelerating rota-rod treadmill and balance beam tasks were observed. The results showed that microinjection of histamine into the cerebellar interpositus nucleus remarkably increased the time that animals balanced steadily on the rota-rod and markedly shortened the duration of passage through the balance beam, whereas GABA significantly depressed motor performances of animals on the rota-rod and beam, and normal saline influenced neither. In addition, administration of selective histamine H(2) receptor antagonist ranitidine considerably decreased the animals' endurance time on rota-rod and noticeably increased the passing time on beam, but selective histamine H(1) receptor antagonist triprolidine showed no effect. Furthermore, microinjection of histamine reversed the inhibitory effects of ranitidine on rota-rod and beam performance. These results demonstrate that histamine enhances rat motor balance and coordination through activation of histamine H(2) receptors in the cerebellar interpositus nucleus and suggest that the hypothalamocerebellar histaminergic projections may play a modulatory role on the cerebellar circuitry to ensure that movements are accurately executed.     

H3 Autoreceptors and muscarinic acetylcholine receptors modulate histamine release in the anterior hypothalamus of freely moving rats

To investigate the modulation of histamine release by autoreceptors and heteroreceptors, the rat anterior hypothalamus was superfused through a push-pull cannula with agonists or antagonists of histamine and acetylcholine muscarinic receptors. Superfusion with the H₃ receptor agonist (R)-α-methylhistamine inhibited, while superfusion with thioperamide (H₃ antagonist) enhanced histamine release. Superfusion with carbachol (a mixed M₁, M₂, M₃ agonist) inhibited the release of histamine. The release of endogenous histamine was enhanced on superfusion with atropine (a mixed M₁, M₂, M₃ antagonist). The M₃ muscarinic antagonist 4-diphenylacetoxy-N-methylpiperidine enhanced the release rate of histamine. It is concluded that in the anterior hypothalamus the release of endogenous histamine is modulated by H₃ autoreceptors. Moreover, acetylcholine released from cholinergic neurons also modulates the release of histamine via M₁ and/or M₃ heteroreceptors.

     

Involvement of the histaminergic system in leptin-induced suppression of food intake

The ob gene product leptin is secreted from white adipose tissue, and may regulate food intake by acting on the hypothalamus in the central nervous system. But the mechanism of this effect is still unclear. The central histaminergic system has been suggested to participate in the control of various physiological functions, particularly in feeding behavior, as it mediates anorectic signals like leptin. Thus, we hypothesized that the central histaminergic system is a target for leptin in its control of feeding. To prove this, we first examined the effect of i.p. administration of alpha-fluoromethylhistidine (FMH), a specific and irreversible inhibitor of histidine decarboxylase, on leptin-induced suppression of food intake in normal C57BL strain mice. Leptin treatment (1.3 mg/kg, i.p.) significantly reduced food intake by 60% of that of control at 6 h and by 84% at 24 h compared with control. When mice were injected with FMH (100 mg/kg, i.p.) before being given leptin, leptin-induced suppression of food intake was abolished and there was no significant difference compared with that of control. Additionally, we further examined the effects of leptin on food intake in mutant mice lacking histamine H, receptors (H1R-KO mice). Leptin injection significantly reduced food intake by 56% of that of control at 6 h and by 79% at 24 h in wild-type mice (WT mice), but not in H1R-KO mice. This finding suggests that leptin affects the feeding behavior through activation of the central histaminergic system via histamine H1 receptors.     

Role of histaminergic H1 and H2 receptors in prolactin release in humans

Histamine is considered as a neurotransmitter, since it is present in hypothalamus and pituitary gland. It has been reported to stimulate prolactin (PRL) release in rats and humans; it seems to be involved in the control of LH release in rats. But cimetidine, an H2 antagonist also induces PRL release in humans. To investigate the relationship between the PRL secretion and possible histaminergic pathways, the response of PRL and LH was studied for 180 minutes in 10 normal subjects (5 men, 5 women) after H1 antagonist (diphenhydramine 50 mg iv), H2 antagonist (cimetidine 300 mg iv) and placebo. Diphenhydramine and placebo injection resulted in a decrease of PRL from 0800 until 11.00 hours, suggesting a spontaneous diurnal variation. Cimetidine induced a short but significant rise of PRL before a similar diurnal secretory pattern. LH levels were unaffected by H1 and H2 antagonists. These data suggest that PRL and LH secretion in humans is unresponsive to H1 histaminergic pathways. The specific action of cimetidine remains to be defined.     

Inhibition of tryptase release from human colon mast cells by histamine receptor antagonists

The main objective of this study was to investigate the ability of histamine receptor antagonists to modulate tryptase release from human colon mast cells induced by histamine. Enzymatically dispersed cells from human colon were challenged with histamine in the absence or presence of the histamine receptor antagonists, and the tryptase release was determined. It was found that histamine induced tryptase release from colon mast cells was inhibited by up to approximately 61.5% and 24% by the H1 histamine receptor antagonist terfenadine and the H2 histamine receptor antagonist cimetidine, respectively, when histamine and its antagonists were added to cells at the same time. The H3 histamine receptor antagonist clobenpropit had no effect on histamine induced tryptase release from colon mast cells at all concentrations tested. Preincubation of terfenadine, cimetidine or clobenpropit with cells for 20 minutes before challenging with histamine did not enhance the ability of these antihistamines to inhibit histamine induced tryptase release. Apart from terfenadine at 100 microg/ml, the antagonists themselves did not stimulate tryptase release from colon mast cells following both 15 minutes and 35 minutes incubation periods. It was concluded that H1 and H2 histamine receptor antagonists were able to inhibit histamine induced tryptase release from colon mast cells. This not only added some new data to our hypothesis of self-amplification mechanisms of mast cell degranulation, but also suggested that combining these two types of antihistamine drugs could be useful for the treatment of inflammatory bowel disease (IBD).     

Serum levels of hypothalamic-pituitary-testicular axis hormones in men with or without prostate cancer or atypical small acinar proliferation

INTRODUCTION:

Substantial controversy exists regarding the association between testosterone serum levels and prostate cancer.

OBJECTIVE:

To evaluate the levels of hypothalamic‐pituitary‐testicular axis hormones in the sera of men with prostate cancer and atypical small acinar proliferation as well as those with normal biopsies.

METHODS:

A study cohort of 186 men with suspected prostate cancer who had undergone transrectal prostate biopsies was used in this study. The patients were divided into the following three groups based on the histology of the biopsy samples: no neoplasia, atypical small acinar proliferation or prostate cancer. Demographic data were also collected. Levels of total testosterone, follicle‐stimulating hormone, luteinizing hormone, prolactin, estradiol, and serum prostate‐specific antigen were measured in blood samples.

RESULTS:

Initially, 123 men were found to be without neoplasia, 26 with atypical small acinar proliferation and 37 with prostate cancer. After a second biopsy was taken from the men diagnosed with atypical small acinar proliferation, the diagnoses were revised: 18 were diagnosed with atypical small acinar proliferation and 45 with prostate cancer. No significant differences between the groups were identified regarding age, smoking history, chronic diseases, body mass index or PSA levels (P>0.05). The mean serum levels of testosterone, follicle‐stimulating hormone, luteinizing hormone, prolactin and estradiol were similar in all of the groups (P>0.05). Furthermore, in individuals with prostate cancer, the Gleason scores and prevalence of hypogonadism were not significantly different (P>0.05).

CONCLUSION:

The present study revealed no difference in the serum levels of testosterone, follicle‐stimulating hormone, luteinizing hormone, prolactin or estradiol in men without neoplasia compared with those with atypical small acinar proliferation or prostate cancer.     

H3 Autoreceptors and muscarinic acetylcholine receptors modulate histamine release in the anterior hypothalamus of freely moving rats

To investigate the modulation of histamine release by autoreceptors and heteroreceptors, the rat anterior hypothalamus was superfused through a push-pull cannula with agonists or antagonists of histamine and acetylcholine muscarinic receptors. Superfusion with the H₃ receptor agonist (R)--methylhistamine inhibited, while superfusion with thioperamide (H₃ antagonist) enhanced histamine release. Superfusion with carbachol (a mixed M₁, M₂, M₃ agonist) inhibited the release of histamine. The release of endogenous histamine was enhanced on superfusion with atropine (a mixed M₁, M₂, M₃ antagonist). The M₃ muscarinic antagonist 4-diphenylacetoxy-N-methylpiperidine enhanced the release rate of histamine. It is concluded that in the anterior hypothalamus the release of endogenous histamine is modulated by H₃ autoreceptors. Moreover, acetylcholine released from cholinergic neurons also modulates the release of histamine via M₁ and/or M₃ heteroreceptors.     

The distribution of histamine H1-receptors in the rat brain: An autoradiographic study

The localization of histamine H₁-receptors in the rat brain was studied at the light microscopic level by quantitative autoradiography. Receptors were labeled in vitro with [³H]mepyramine. The autoradiograms revealed a widespread distribution of these receptors throughout the brain. Areas with high receptor concentrations are: the bed nucleus of the stria terminalis, polymorphic layer of the hilus of the area dentata, ventromedial nuclei of the hypothalamus, pontine nuclei and other nuclei in the pons, the nucleus tractus solitarii and the dorsal motor nucleus of the vagus nerve. Possible relationships of the distributions of histamine H₁-receptors with (a) specific anatomical systems, (b) the known distribution of histaminergic terminals and (c) the central pharmacological effects of histamine and antihistaminics are discussed.     

Stress,the neuroendocrine system and mast cells: current understanding of their role in psoriasis

Psychological stress can activate the hypothalamic–pituitary–adrenal axis and sensory nerves in the brain and skin, resulting in the release of neuroendocrine and neural mediators such as, corticotropin-releasing hormone, neuropeptides, neurotrophins and α-melanocyte-stimulating hormone. These factors can activate mast cells to release proinflammatory mediators and some of them, for example, histamine, tryptase and nerve growth factor, can stimulate sensory C-fibers. Since corticotropin-releasing hormone, sensory nerves and mast cell numbers are increased in the psoriatic lesion, a feedforward loop can exist potentiating the inflammation. Studies in rats and mice have shown that mast cells are activated during standardized stress through corticotropin-releasing hormone and sensory nerves. Therefore, the role of stress, the neuroendocrine system and mast cells in psoriasis is discussed in this article.