Organization of the histaminergic system in adult zebrafish (Danio rerio) brain: Neuron number, location, and cotransmitters

Histamine is an essential factor in the ascending arousal system (AAS) during motivated behaviors. Histamine and hypocretin/orexin (hcrt) are proposed to be responsible for different aspects of arousal and wakefulness, histamine mainly for cognitive and motivated behaviors. In this study we visualized the entire histaminergic neuron population in adult male and female zebrafish brain and quantified the histaminergic neuron numbers. There were 40–45 histaminergic neurons in both male and female zebrafish brain. Further, we identified cotransmitters of histaminergic neurons in the ventrocaudal hypothalamus, i.e., around the posterior recess (PR) in adult zebrafish. Galanin, γ‐aminobutyric acid (GABA), and thyrotropin‐releasing hormone (TRH) were colocalized with histamine in some but not all neurons, a result that was verified by intracerebroventricular injections of colchicine into adult zebrafish. Fibers immunoreactive (ir) for galanin, GABA, TRH, or methionine‐enkephalin (mENK) were dense in the ventrocaudal hypothalamus around the histaminergic neurons. In histamine‐ir fibers TRH and galanin immunoreactivities were also detected in the ventral telencephalon. All these neurotransmitters are involved in maintaining the equilibrium of the sleep–wake state. Our results are in accordance with results from rats, further supporting the use of zebrafish as a tool to study molecular mechanisms underlying complex behaviors. J. Comp. Neurol. 520:3827–3845, 2012. © 2012 Wiley Periodicals, Inc.     

Histamine H3 receptor in primary mouse microglia inhibits chemotaxis,phagocytosis, and cytokine secretion

Histamine is a physiological amine which initiates a multitude of physiological responses by binding to four known G‐protein coupled histamine receptor subtypes as follows: histamine H₁ receptor (H₁R), H₂R, H₃R, and H₄R. Brain histamine elicits neuronal excitation and regulates a variety of physiological processes such as learning and memory, sleep–awake cycle and appetite regulation. Microglia, the resident macrophages in the brain, express histamine receptors; however, the effects of histamine on critical microglial functions such as chemotaxis, phagocytosis, and cytokine secretion have not been examined in primary cells. We demonstrated that mouse primary microglia express H₂R, H₃R, histidine decarboxylase, a histamine synthase, and histamine N‐methyltransferase, a histamine metabolizing enzyme. Both forskolin‐induced cAMP accumulation and ATP‐induced intracellular Ca²⁺ transients were reduced by the H₃R agonist imetit but not the H₂R agonist amthamine. H₃R activation on two ubiquitous second messenger signalling pathways suggests that H₃R can regulate various microglial functions. In fact, histamine and imetit dose‐dependently inhibited microglial chemotaxis, phagocytosis, and lipopolysaccharide (LPS)‐induced cytokine production. Furthermore, we confirmed that microglia produced histamine in the presence of LPS, suggesting that H₃R activation regulate microglial function by autocrine and/or paracrine signalling. In conclusion, we demonstrate the involvement of histamine in primary microglial functions, providing the novel insight into physiological roles of brain histamine. GLIA 2015;63:1213–1225     

Distribution of organic cation transporter 3, a corticosterone‐sensitive monoamine transporter,in the rat brain

Organic cation transporter 3 (OCT3) is a high‐capacity, low‐affinity transporter that mediates bidirectional, sodium‐independent transport of dopamine, norepinephrine, epinephrine, serotonin, and histamine. OCT3‐mediated transport is directly inhibited by corticosterone, suggesting a potential role for the transporter in mediating some of the effects of stress and glucocorticoids on monoaminergic neurotransmission. To elucidate the importance of OCT3 in clearance of extracellular monoamines in the brain, we used immunohistochemical techniques to describe the distribution of OCT3‐like‐immunoreactive (OCT3‐ir) cells throughout the rostrocaudal extent of adult male rat brains. OCT3‐ir cell bodies were widely distributed throughout the brain, with the highest densities observed in the superior and inferior colliculi, islands of Calleja, subiculum, lateral septum, lateral and dorsomedial hypothalamic nuclei, and granule cell layers of the main and accessory olfactory bulbs, the cerebellum, and the retrosplenial granular cortex. OCT3‐ir cells and/or fibers were also observed in circumventricular organs, and OCT3‐ir ependymal cells were observed in the linings of all cerebral ventricles. The widespread distribution of OCT3‐ir cell bodies, including regions receiving dense monoaminergic projections, suggests an important role for this transporter in regulating extracellular concentrations of monoamines in the rat brain and is consistent with the hypothesis that corticosterone‐induced inhibition of OCT3‐mediated transport may contribute to effects of acute stress or corticosterone on monoaminergic neurotransmission. J. Comp. Neurol. 512:529–555, 2009. © 2008 Wiley‐Liss, Inc.     

Histamine‐N‐methyl transferase polymorphism and risk for multiple sclerosis

Background: Histamine N‐methyltransferase (HNMT) is the main metabolizing enzyme of histamine (a mediator of inflammation implicated in the pathogenesis of multiple sclerosis‐MS) in the CNS. We have investigated the possible association between a single nucleotide polymorphism of the HNMT (chromosome 2q22.1), that causes the amino acid substitution Thr105Ile (decreasing enzyme activity) and the risk for MS. Methods: We studied the frequency of the HNMT genotypes and allelic variants in 228 MS patients and 295 healthy controls using a PCR‐RLFP method. Results: The frequencies of the HNMT genotypes and allelic variants did not differ significantly between MS patients and controls, and were unrelated with the age of onset of MS, gender, and course of MS. Conclusion: The HNMT polymorphism is not related with the risk for MS.     

Role of histamine and its receptors in cerebral ischemia

Histamine is recognized as a neurotransmitter or neuromodulator in the brain, and it plays a major role in the pathogenic progression after cerebral ischemia. Extracellular histamine increases gradually after ischemia, and this may come from histaminergic neurons or mast cells. Histamine alleviates neuronal damage and infarct volume, and it promotes recovery of neurological function after ischemia; the H1, H2, and H3 receptors are all involved. Further studies suggest that histamine alleviates excitotoxicity, suppresses the release of glutamate and dopamine, and inhibits inflammation and glial scar formation. Histamine may also affect cerebral blood flow by targeting to vascular smooth muscle cells, and promote neurogenesis. Moreover, endogenous histamine is an essential mediator in the cerebral ischemic tolerance. Due to its multiple actions, affecting neurons, glia, vascular cells, and inflammatory cells, histamine is likely to be an important target in cerebral ischemia. But due to its low penetration of the blood-brain barrier and its wide actions in the periphery, histamine-related agents, like H3 antagonists and carnosine, show potential for cerebral ischemia therapy. However, important questions about the molecular aspects and pathophysiology of histamine and related agents in cerebral ischemia remain to be answered to form a solid scientific basis for therapeutic application.     

Binding of [3H]histamine to receptor sites in rat brain.

[³H]Histamine binds to crude synaptic membranes from rat brain with a dissociation constant of 0.683 μm. The hypothalamus shows the most binding among five other brain regions. Binding of [³H]histamine is not affected by noradrenaline, dopamine, or serotonin; however, it is inhibited more by H₂ receptor than by H₁ receptor agents, suggesting the prevalence of H₂-histamine receptors in brain.     

Heterogeneity of histaminergic neurons in the tuberomammillary nucleus of the rat

Histaminergic neurons of the hypothalamic tuberomammillary nuclei (TMN) send projections to the whole brain. Early anatomical studies described histaminergic neurons as a homogeneous cell group, but recent evidence indicates that histaminergic neurons are heterogeneous and organized into distinct circuits. We addressed this issue using the double‐probe microdialysis in freely moving rats to investigate if two compounds acting directly onto histaminergic neurons to augment cell firing [thioperamide and bicuculline, histamine H₃‐ and γ‐aminobutyric acid (GABA)_A‐receptor (R) antagonists, respectively] may discriminate groups of histaminergic neurons impinging on different brain regions. Intra‐hypothalamic perfusion of either drug increased histamine release from the TMN and cortex, but not from the striatum. Thioperamide, but not bicuculline, increased histamine release from the nucleus basalis magnocellularis (NBM), bicuculline but not thioperamide increased histamine release from the nucleus accumbens (NAcc). Intra‐hypothalamic perfusion with thioperamide increased the time spent in wakefulness. To explore the local effects of H₃‐R blockade in the histaminergic projection areas, each rat was implanted with a single probe to simultaneously administer thioperamide and monitor local changes in histamine release. Thioperamide increased histamine release from the NBM and cortex significantly, but not from the NAcc or striatum. The presence of H₃‐Rs on histaminergic neurons was assessed using double‐immunofluorescence with anti‐histidine decarboxylase antibodies to identify histaminergic cells and anti‐H₃‐R antibodies. Confocal analysis revealed that all histaminergic somata were immunopositive for the H₃‐R. This is the first evidence that histaminergic neurons are organized into functionally distinct circuits that influence different brain regions, and display selective control mechanisms.     

Histamine and prostanoid receptors on glial cells

Glial cells in vitro express at least two types (H₁ and H₂) of histamine receptors and three types (EP, FP, and TP) of prostanoid receptors. The receptors expressed by glial cells differ according to the cell type and source in the brain. Further-more primary astrocytes of same type derived from the same brain region are composed of heterogeneous subpopulations expressing different subsets of receptors. Fura-2 based Ca²⁺ microscopy revealed that astrocyte processes are important sites for histamine-induced Ca²⁺ signalling. Histamine and prostanoid receptors on glial cells may play important roles in the actions of histamine and prostanoids in the central nervous system. © 1994 Wiley-Liss, Inc.     

Signal transduction by histamine in the cerebellum and its modulation by <Emphasis Type="Italic">N</Emphasis>-methyltransferase

Histamine has been suggested to have roles as a neurotransmitter or a neuromodulator. Direct fiber connections between the hypothalamus and the cerebellum have recently been demonstrated and it is suggested that the cerebellum is involved in the control of autonomic and emotional functions. These fibers include histaminergic fibers. The components of histaminergic signal transmission are demonstrated in the cerebellum as follows: (1) the histaminergic fibers are visualized immunohistochemically in the cerebellar cortex of rat, guinea pig and human; (2) histamine H1 receptors are visualized by autoradiographic studies in the molecular layer of mouse and guinea pig. In situ hybridization study also detects the expression of H1 receptors in the Purkinje cells. H2 receptors are expressed in the Purkinje cells and granule cells of guinea pig; and (3) the application of histamine to the slices of guinea pig or rat cerebellar cortex elicits an increase in the turnover of phosphoinositides, so H1 receptors in the cerebellum are functional. Additionally, we have recently shown in the guinea pig that Purkinje cells express one of the histamine inactivating enzymes, and that inhibition of this enzyme enhances phosphoinositide turnover by histamine. Therefore, all the components of histaminergic neurotransmission are demonstrated in the cerebellum. These data suggest that histamine is involved in the signal transmission from the hypothalamus to the cerebellum. Here we review each component of histaminergic neurotransmission in the cerebellum.     

Experimental cerebral infarction in primates: Regional changes in brain histamine content

Summary Histamine levels in different regions of the brain in the primateMacaco, Radiata were studied following experimental infarction induced in the basal ganglia by coagulation of the middle cerebral artery. In the basal ganglia an elevation of histamine level was seen probably due to proliferation of mast cells. In the hypothalamus, a main constituent of the ascending histaminergic neuronal pathway, a sharp rise in histamine content occurred in infarcted as well as sham-operated animals: this probably reflects nonspecific stress-related alterations. In contrast, the cortical area of the ischemie hemisphere showed a higher elevation of histamine, demonstrating that infarction in one region can cause widespread specific changes in histaminergic systems remote from the infarct. The rise in histamine level at the ischemie site could evoke an increase in microcirculation which might aggravate cerebral edema, while changes in the remote regions may be responsible for some of the neurological deficits following stroke.Presented in part at the Third Annual Meeting of the European Society for Neurochemists, Bled, Yugoslavia, 1980.     

Histamine turnover in regions of rat brain

Rapid and complete inhibition of monoamine oxidase by pargyline produced linear increases in the content of the histamine metabolite, tele-methylhistamine (t-MH), in 9 regions of rat brain 2 and 4 h after drug administration. The treatment had little or no effect on the histamine content of these regions. As histamine methylation is the major metabolic pathway of histamine in brain, the rate of increase in brain t-MH content after complete inhibition of its metabolism provides an estimate of histamine turnover. Histamine turnover rates varied over 46-fold among regions, from cerebellum (0.029 nmol/g . h) to hypothalamus (1.33 nmol/g . h), similar to those reported for norepinephrine and serotonin. Turnover rates were highly correlated with control t-MH levels (r = 0.97) and control histamine levels (r = 0.84). Rate constants were highest in the caudate nucleus and frontal cortex, equivalent to a half-life of about 11 min in these regions. While hypothalamic histamine had the highest turnover rate, the rate constant for histamine in this region was among the lowest in brain, perhaps consistent with the presence of histaminergic cell bodies. Histamine turnover rates may be indicative of the activity of histamine-synthesizing neurons, and their determination will facilitate understanding of histamine in brain.     

Neuronal and vascular localization of histamine N-methyltransferase in the bovine central nervous system

Histamine N-methyltransferase (HMT) (EC 2.1.1.8) plays a crucial role in the inactivation of the neurotransmitter histamine in the CNS. However, the localization of HMT remains to be determined. In the present study, we investigated immunohistochemical localization of HMT in the bovine CNS using a polyclonal antibody against bovine HMT. The HMT-like immunoreactivity was observed mainly in neurons. Strongly immunoreactive neurons were present in the oculomotor nucleus and ruber nucleus in the midbrain, the facial nucleus in the pons, the dorsal vagal nucleus and hypoglossal nucleus in the medulla oblongata and in the anterior horn as well as intermediolateral zone of the spinal cord. Intermediately immunoreactive neurons were present in the piriform cortex and the inferior olivary nucleus. The grey matter of the forebrain regions was diffusely and faintly stained. In the cerebellum and the striatum, the nerve fibres in the white matter were positive. The tuberomammillary nucleus, where histaminergic neurons are present, were weakly positive. The other immunoreactive structures in the CNS were blood vessels. Almost all of the blood vessel walls, irrespective of whether they were arterial or venous, were variably stained. The glial fibrillary acidic protein- (GFAP-) immunoreactive astrocytes were not stained. These findings indicated that histamine released from histaminergic nerve terminals or varicose fibres is methylated mainly in postsynaptic or extrasynaptic neurons rather than in astrocytes. The localization of HMT in the blood vessel wall may mean that blood-borne histamine and histamine released from mast cells associated with the blood vessels are catabolized in this structure.     

Inverse agonist histamine H3 receptor PET tracers labelled with carbon‐11 or fluorine‐18

Two histamine H3 receptor (H3R) inverse agonist PET tracers have been synthesized and characterized in preclinical studies. Each tracer has high affinity for the histamine H3 receptor, has suitable lipophilicity, and neither is a substrate for the P‐glycoprotein efflux pump. A common phenolic precursor was used to synthesize each tracer with high specific activity and radiochemical purity by an alkylation reaction using either [¹¹C]MeI or [¹⁸F]FCD₂Br. Autoradiographic studies in rhesus monkey and human brain slices showed that each tracer had a widespread distribution with high binding densities in frontal cortex, globus pallidus and striatum, and lower uptake in cerebellum. The specificity of this expression pattern was demonstrated by the blockade of the autoradiographic signal by either the H3R agonist R‐α‐methylhistamine or a histamine H3R inverse agonist. In vivo PET imaging studies in rhesus monkey showed rapid uptake of each tracer into the brain with the same distribution seen in the autoradiographic studies. Each tracer could be blocked by pretreatment with a histamine H3R inverse agonist giving a good specific signal. Comparison of the in vitro metabolism of each compound showed slower metabolism in human liver microsomes than in rhesus monkey liver microsomes, with each compound having a similar clearance rate in humans. The in vivo metabolism of 1b in rhesus monkey showed that at 60 min, ～35% of the circulating counts were due to the parent. These tracers are very promising candidates as clinical PET tracers to both study the histamine H3R system and measure receptor occupancy of H3R therapeutic compounds. Synapse 63:1122–1132, 2009. © 2009 Wiley‐Liss, Inc.     

The histaminergic system in human thalamus: correlation of innervation to receptor expression

The mRNA expression of three histamine receptors (H1, H2 and H3) and H1 and H3 receptor binding were mapped and quantified in normal human thalamus by in situ hybridization and receptor binding autoradiography, respectively. Immunohistochemistry was applied to study the distribution of histaminergic fibres and terminals in the normal human thalamus. mRNAs for all three histamine receptors were detected mainly in the dorsal thalamus, but the expression intensities were different. Briefly, H1 and H3 receptor mRNAs were relatively enriched in the anterior, medial, and part of the lateral nuclei regions; whereas the expression level was much lower in the ventral and posterior parts of the thalamus, and the reticular nucleus. H2 receptor mRNA displayed in general very low expression intensity with slightly higher expression level in the anterior and lateropolar regions. H1 receptor binding was mainly detected in the mediodorsal, ventroposterolateral nuclei, and the pulvinar. H3 receptor binding was detected mainly in the dorsal thalamus, predominantly the periventricular, mediodorsal, and posterior regions. Very high or high histaminergic fibre densities were observed in the midline nuclear region and other nuclei next to the third ventricle, ventroposterior lateral nucleus and medial geniculate nucleus. In most of the core structures of the thalamus, the fibre density was very low or absent. The results suggest that histamine in human brain regulates tactile and proprioceptory thalamocortical functions through multiple receptors. Also, other, e.g. visual areas and those not making cortical connections expressed histamine receptors and contained histaminergic nerve fibres.     

Ca2+ transients in astrocyte fine processes occur via Ca2+ influx in the adult mouse hippocampus

Astrocytes display complex morphologies with an array of fine extensions extending from the soma and the primary thick processes. Until the use of genetically encoded calcium indicators (GECIs) selectively expressed in astrocytes, Ca²⁺ signaling was only examined in soma and thick primary processes of astrocytes where Ca²⁺‐sensitive fluorescent dyes could be imaged. GECI imaging in astrocytes revealed a previously unsuspected pattern of spontaneous Ca²⁺ transients in fine processes that has not been observed without chronic expression of GECIs, raising potential concerns about the effects of GECI expression. Here, we perform two‐photon imaging of Ca²⁺ transients in adult CA1 hippocampal astrocytes using a new single‐cell patch‐loading strategy to image Ca²⁺‐sensitive fluorescent dyes in the cytoplasm of fine processes. We observed that astrocyte fine processes exhibited a high frequency of spontaneous Ca²⁺ transients whereas astrocyte soma rarely showed spontaneous Ca²⁺ oscillations similar to previous reports using GECIs. We exploited this new approach to show these signals were independent of neuronal spiking, metabotropic glutamate receptor (mGluR) activity, TRPA1 channels, and L‐ or T‐type voltage‐gated calcium channels. Removal of extracellular Ca²⁺ almost completely and reversibly abolished the spontaneous signals while IP₃R2 KO mice also exhibited spontaneous and compartmentalized signals, suggesting they rely on influx of extracellular Ca²⁺. The Ca²⁺ influx dependency of the spontaneous signals in patch‐loaded astrocytes was also observed in astrocytes expressing GCaMP3, further highlighting the presence of Ca²⁺ influx pathways in astrocytes. The mechanisms underlying these localized Ca²⁺ signals are critical for understanding how astrocytes regulate important functions in the adult brain. GLIA 2016;64:2093–2103     

Structure of the human histamine H3 receptor gene (HRH3) and identification of naturally occurring variations

Summary. Neurotransmitter release is modulated by presynaptic histamine H₃ receptors located on histaminergic, noradrenergic and other nonhistaminergic neurons of the central and peripheral nervous system. Here, we report the determination of the structure of the human histamine H₃ receptor gene (HRH3) and the identification of a missense mutation (Ala280Val) in a patient with Shy-Drager syndrome. The coding region of the gene consists of three exons interrupted by two introns of approximately 1 kb in size. Exon boundaries only partly correspond to transmembrane domain organization. The homozygous Ala280Val variation in the third intracellular loop of the histamine H₃ receptor of a patient with Shy-Drager syndrome may be related to the etiology of the illness due to altered norepinephrine release. Furthermore, knowledge of the gene structure allows the verification of alternative splicing of the receptor. The corresponding histamine H₃ receptor isoforms as reported for the guinea pig and rat histamine H₃ receptor in different brain regions are not found in the human brain. Received July 11, 2001; accepted November 30, 2001     

中枢组胺能系统研究的新进展

近年来对于中枢组胺能系统的研究 ,在组胺受体的分子生物学、组胺能系统的生理功能 ,以及组胺能神经传递功能的紊乱与某些脑疾病之间的关系等问题上取得了较大进展 ,本文对这些进展作一简要的综述。     

Expression of the H3 receptor in the developing CNS and brown fat suggests novel roles for histamine

Histamine and histamine receptors have been implicated in signaling mechanisms in developmental processes in the brain and peripheral organs. Pharmacological studies have also implied that the histamine H(3) receptor, in addition to acting as a presynaptic auto- and heteroreceptor in the central nervous system, is active in peripheral tissues. We show that detectable histamine H(3)-receptor expression during development and in adult rat is restricted to specific areas of the brain and to adipocytes and the capillary network in brown adipose tissue. Histamine H(3)-receptor mRNA expression was not detected in other internal organs studied, or in spinal or sympathetic chain ganglia. These results support a histaminergic involvement in brain development through activation of the histamine H(3) receptor and indicate a possible novel involvement of the histamine H(3) receptor as a mediator of the effects of histamine in thermogenesis in brown adipose tissue.     

Decreased histamine H1 receptor binding in the brain of depressed patients

The central histaminergic neuron system modulates the wakefulness, sleep-awake cycle, appetite control, learning and memory, and emotion. Previous studies have reported changes in neuronal histamine release and its metabolism under stress conditions in the mammalian brain. In this study, we examined, using positron emission tomography (PET) and [(11)C]-doxepin, whether the histaminergic neuron system is involved in human depression. Cerebral histamine H1 receptor (H(1)R) binding was measured in 10 patients with major depression and in 10 normal age-matched subjects using PET and [(11)C]-doxepin. Data were calculated by a graphical analysis on voxel-by-voxel and ROI (region of interests) basis. Binding potential (BP) values for [(11)C]-doxepin binding in the frontal and prefrontal cortices, and cingulate gyrus were significantly lower in the depressed patients than those in the normal control subjects. There was no area of the brain where [(11)C]-doxepin binding was significantly higher in the depressed patients than in the controls. ROI-based analysis also revealed that BP values for [(11)C]-doxepin binding in the frontal cortex and cingulate gyrus decreased in proportion to self-rating depressive scales scores. The results of this study demonstrate that depressed patients have decreased brain H(1)R binding and that this decrease correlates with the severity of depression symptoms. It is therefore suggested that the histaminergic neuron system plays an important role in the pathophysiology of depression and that its modulation may prove to be useful in the treatment of depression.     

Histamine facilitates in vivo thalamocortical long-term potentiation in the mature visual cortex of anesthetized rats

Recent evidence indicates that the mature central visual system retains a higher degree of plasticity than traditionally assumed. However, little is known regarding the neuromodulatory factors that influence plasticity in the adult primary visual cortex (V1). We investigated the role of histamine, one of the neuromodulators that densely innervate all neocortical fields, in modulating plasticity of V1 by examining thalamocortical long-term potentiation (LTP). Theta-burst stimulation of the lateral geniculate nucleus of urethane-anesthetized rats resulted in potentiation of the field postsynaptic potential recorded in the superficial layers of V1. Histamine (0.01–10 m m ), applied locally in V1 by reverse microdialysis, produced a clear, dose-dependent enhancement of LTP. In addition, histamine also allowed a weak theta-burst induction protocol, that by itself failed to induce significant synaptic potentiation, to produce stable LTP. The effect of histamine to facilitate LTP was largely resistant to blockade of H₁[chlorpheniramine, 5 and 10 mg/kg, intraperitoneal (i.p.)] or H₂ receptors (cimetidine, 10 mg/kg, zolantidine, 5 mg/kg, i.p.). However, arcaine sulfate salt (10 mg/kg, i.p.), a blocker of the polyamine binding site of the N -methyl- d -aspartate (NMDA) receptor, completely antagonized the LTP amplification induced by histamine, suggesting that it acts via a direct modulation of NMDA receptors, rather than histaminergic receptor activation. The present experiments provide the first demonstration of a histaminergic influence on neocortical synaptic plasticity in vivo and show that cortical histaminergic activation acts to lower the induction threshold and increase the degree of plasticity in the mature thalamocortical visual system.