Histaminergic Neurotransmission Research Articles

Anxiety and cognition in female histidine decarboxylase knockout ( Hdc−/−) mice

The role of histamine in brain function has been studied using histidine decarboxylase (HDC) deficient male mice. As the effects of HDC deficiency on brain function might be sex-dependent, we behaviorally analyzed Hdc −/− and control female mice. Compared to female control mice, Hdc −/− female mice showed hypoactivity, increased measures of anxiety, impairments in water-maze performance, but enhanced passive avoidance memory retention. Following behavioral testing, arginine vasopression (AVP) immunoreactivity was higher in the dorsal hypothalamus and central and basolateral nuclei of the amygdala of Hdc −/− than Hdc +/+ mice. Finally, MAP2 immunoreactivity in the hippocampal CA1 region correlated positively with measures of anxiety in the open-field and light–dark tests and negatively with performance during the hidden sessions of the water-maze. As the effects of HDC deficiency on object recognition, water-maze, and rotorod performance, were sex-dependent, it is important to consider potential effects of sex in the interpretation of the role of histaminergic neurotransmission in brain function.

Drosophila tan Encodes a Novel Hydrolase Required in Pigmentation and Vision

Many proteins are used repeatedly in development, but usually the function of the protein is similar in the different contexts. Here we report that the classical Drosophila melanogaster locus tan encodes a novel enzyme required for two very different cellular functions: hydrolysis of N-β-alanyl dopamine (NBAD) to dopamine during cuticular melanization, and hydrolysis of carcinine to histamine in the metabolism of photoreceptor neurotransmitter. We characterized two tan-like P-element insertions that failed to complement classical tan mutations. Both are inserted in the 5′ untranslated region of the previously uncharacterized gene CG12120, a putative homolog of fungal isopenicillin-N N-acyltransferase (EC 2.3.1.164). Both P insertions showed abnormally low transcription of the CG12120 mRNA. Ectopic CG12120 expression rescued tan mutant pigmentation phenotypes and caused the production of striking black melanin patterns. Electroretinogram and head histamine assays indicated that CG12120 is required for hydrolysis of carcinine to histamine, which is required for histaminergic neurotransmission. Recombinant CG12120 protein efficiently hydrolyzed both NBAD to dopamine and carcinine to histamine. We conclude that D. melanogaster CG12120 corresponds to tan. This is, to our knowledge, the first molecular genetic characterization of NBAD hydrolase and carcinine hydrolase activity in any organism and is central to the understanding of pigmentation and photoreceptor function.

Blockage of histamine H1 receptor attenuates social isolation-induced disruption of prepulse inhibition: a study in H1 receptor gene knockout mice

Histaminergic neurotransmission has been implicated in the pathophysiology of stress-related psychiatric diseases. Although several atypical antipsychotics are potent H1 antagonists, the clinical significance of interaction between atypical antipsychotics and H1 receptors is still unknown. In this study, we investigated the effects of H1 receptors blockage on social isolation-induced behavioral changes in H1 receptor gene knockout (H1KO) mice and their wild-type (WT) mice. Both H1KO and their WT mice were subjected to 4-week social isolation rearing after weaning (21 postnatal days). After the 4-week isolation period, mice behavioral changes were evaluated using behavioral tests. Locomotor activity in home cages was significantly lower in isolation-reared WT mice than in socially reared WT mice. However, no change in locomotor activity was observed between socially and isolation-reared H1KO mice. Social isolation significantly impaired prepulse inhibition (PPI) of startle response in WT mice but not in H1KO mice. In addition, social isolation significantly impaired spatial learning and memory in WT mice but not in H1KO mice. Furthermore, H1KO mice treated with methamphetamine (METH) showed no enhancement in isolation-induced disruption of PPI. A neurochemical study revealed that isolation-reared WT mice had significantly lower dopamine (DA) levels and slightly increased DA turnover in the cortex than socially reared WT mice. Conversely, isolation-reared H1KO mice showed significantly higher DA contents as compared with socially reared H1KO mice. The results of our study indicate that blockage of H1 receptor-mediated neurotransmission attenuates social isolation-induced behavioral changes and that the therapeutic effects of atypical antipsychotics are mediated, at least in part, by interaction with H1 receptors in the brain.

Mouse behavioural analysis in systems biology

Molecular techniques allowing in vivo modulation of gene expression have provided unique opportunities and challenges for behavioural studies aimed at understanding the function of particular genes or biological systems under physiological or pathological conditions. Although various animal models are available, the laboratory mouse (Mus musculus) has unique features and is therefore a preferred animal model. The mouse shares a remarkable genetic resemblance and aspects of behaviour with humans. In this review, first we describe common mouse models for behavioural analyses. As both genetic and environmental factors influence behavioural performance and need to be carefully evaluated in behavioural experiments, considerations for designing and interpretations of these experiments are subsequently discussed. Finally, common behavioural tests used to assess brain function are reviewed, and it is illustrated how behavioural tests are used to increase our understanding of the role of histaminergic neurotransmission in brain function.

The H 3 receptor protean agonist proxyfan enhances the expression of fear memory in the rat

Consolidation of fear memory requires neural changes to occur in the basolateral amygdala (BLA), including modulation of histaminergic neurotransmission. We previously demonstrated that local blockade or activation of histamine H 3 receptors in the BLA impaired or ameliorated, respectively, retention of fear memory. The histamine H 3 receptor is a G-protein-coupled receptor (GPCR) displaying high constitutive activity that regulates histamine neurons in the brain. Proxyfan is a high-affinity histamine H 3 receptor protean agonist exhibiting the full spectrum of pharmacological activities, from full agonist to full inverse agonist depending on the competition between constitutively active and quiescent H 3 receptors in a given tissue or brain region. Therefore, protean agonists are powerful tools to investigate receptor conformation and may be useful in designing specific compounds selective for the various receptor conformations. In the present study we examined the effect of post-training, systemic or intra-BLA injections of proxyfan on contextual fear memory. Rats receiving intra-BLA, bilateral injections of 1.66 ng proxyfan immediately after fear conditioning showed stronger memory for the context-footshock association, as demonstrated by longer freezing assessed at retention performed 72 hr later compared to controls. Comparable results were obtained when doses as low as 0.04 mg/kg of proxyfan were injected systemically. Hence, our results suggest that proxyfan behaves as an H 3 receptor agonist with a low level of constitutive activity of the H 3 receptor in the rat BLA.

Immunocytochemistry of histamine in the brain of the locust Schistocerca gregaria.

Histamine serves a neurotransmitter role in arthropod photoreceptor neurons, but is also present in a small number of interneurons throughout the nervous system. In search of a suitable model system for the analysis of histaminergic neurotransmission in insects, we mapped the distribution of histamine in the brain of the desert locust Schistocerca gregaria by immunocytochemistry. In the optic lobe, apparently all photoreceptor cells of the compound eye with projections to the lamina and medulla showed intense immunostaining. Photoreceptors of the dorsal rim area of the eye had particularly large fiber diameters and gave rise to uniform varicose immunostaining throughout dorsal rim areas of the lamina and medulla. In the locust midbrain 21 bilateral pairs of histamine-immunoreactive interneurons were found, and 13 of these were reconstructed in detail. While most neuropil areas contained a dense meshwork of immunoreactive processes, immunostaining in the antennal lobe and in the calyces of the mushroom body was sparse and no staining occurred in the pedunculus and lobes of the mushroom body, in the protocerebral bridge, and in the lower division of the central body. A prominent group of four immunostained neurons had large cell bodies near the median ocellar nerve root and descending axonal fibers. These neurons are probably identical to previously identified primary commissure pioneer neurons of the locust brain. The apparent lack in the desert locust of certain histamine-immunoreactive neurons which were reported in the migratory locust may be responsible for differences in the physiological role of histamine between both species.

Role of orexin and prostaglandin E(2) in activating histaminergic neurotransmission.

Although the molecular mechanisms underlying the control of sleep have been extensively studied in the past, relatively little attention has been paid to the regulatory mechanisms involved in the maintenance and control of wakefulness until today. In this article, recent developments leading to our better understanding of the arousal system will be reviewed with the main emphasis on three messengers: histamine, prostaglandin E(2) and orexin. The results reported herein may provide new insights into the molecular mechanisms of sleep-wake regulation and may lead to the development of new anti-sleep drugs as well as new hypnotic agents.

Alcoholics show altered histaminergic neurotransmission in several cortical areas--preliminary report.

Alcoholics show altered histaminergic neurotransmission in several cortical areas--preliminary report.

Metabotropic histamine receptors—nothing for invertebrates?

Histamine, a major neurotransmitter both in vertebrates and invertebrates, transmits its actions through a set of well-known receptors. In vertebrates, these receptors belong to the family of G-protein-coupled receptors. In invertebrates, the few well-characterized actions of histamine are transmitted through ionotropic histamine receptors. To evaluate if metabotropic histamine receptors are part of the invertebrate histaminergic signaling cascade, I identified the complete set of metabotropic bioamine receptors from two invertebrates, whose entire genome has been sequenced: the fruitfly Drosophila melanogaster and the soil nematode Caenorhabditis elegans. A comparison with representatives of all groups of metabotropic bioamine receptors from vertebrates and invertebrates showed that none of these receptors clusters together with any of the four groups of vertebrate histamine receptors. This implies that no direct homologues to vertebrate metabotropic histamine receptor are present in invertebrates. Therefore, it is reasonable to account that the histaminergic neurotransmission in invertebrates is exclusively transmitted through ionotropic histamine receptors and that metabotropic histamine receptors evolved after the split between vertebrates and invertebrates.

Signal transduction by histamine in the cerebellum and its modulation by N-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.

Light induces cortical activation and yawning in rats

We examined the effects of light stimulation on cortical activation and yawning response in anesthetized, spontaneously breathing rats. Cortical activation was assessed by means of an electrocorticogram (ECoG) and yawning response was evaluated by monitoring an intercostal electromyogram as an index of inspiratory activity and a digastric electromyogram as an indicator of mouth opening. Light stimulation elicited an arousal shift in the ECoG to faster rhythms. This arousal response was followed by a single large inspiration with mouth opening, i.e. a yawning response. Higher light intensity significantly reduced the onset latency of the arousal/yawning response. Pretreatment with pyrilamine, an H1-histamine receptor antagonist, injected into the lateral ventricle blocked both the cortical activation and the yawning response induced by light stimulation, suggesting a role of brain histaminergic neurotransmission in modulating the light-induced arousal/yawning responses.

Effect of some antiepileptic drugs on brain histaminergic systems in the rat.

The effects of three different types of antiepileptics on brain histamine turnover were studied. Histamine (HA) has been proposed to have anticonvulsive properties [1]. However, it is not known whether antiepileptic drugs have any effect on histaminergic neurotransmission. The effect of gabapentin on neurotransmitters, other than HA, has been studied previously in vitro [2, 3]. The aim of this study was to evaluate possible changes in histaminergic mechanisms related to treatment with phenytoin, gabapentin or ethosuximide in the rat. Effects of these different types of antiepileptics on brain histamine and methylhistamine concentrations were studied in vivo.

Development of a new class of nonimidazole histamine H(3) receptor ligands with combined inhibitory histamine N-methyltransferase activity.

In search of novel ways to enhance histaminergic neurotransmission in the central nervous system, a new class of nonimidazole histamine H(3) receptor ligands were developed that simultaneously possess strong inhibitory activity on the main histamine metabolizing enzyme, histamine N-methyltransferase (HMT). The novel compounds contain an aminoquinoline moiety, which is an important structural feature for HMT inhibitory activity, connected by different spacers to a piperidino group (for H(3) receptor antagonism). Variation of the spacer structure provides two different series of compounds. One series, having only an alkylene spacer between the basic centers, led to highly potent HMT inhibitors with moderate to high affinity at human histamine H(3) receptors. The second series possesses a p-phenoxypropyl spacer, which may be extended by another alkylene chain. This latter series also showed strong inhibitory activity on HMT, and in most cases, the H(3) receptor affinity even surpassed that of the first series. One of the most potent compounds with this dual mode of action is 4-(4-(3-piperidinopropoxy)phenylamino)quinoline (34) (hH(3), K(i) = 0.09 nM; HMT, IC(50) = 51 nM). This class of compounds showed high antagonist potency and good H(3) receptor selectivity in functional assays in guinea pig on H(1), H(2), and H(3) receptors. Because of low or missing in vivo activity of two selected compounds, the proof of concept of these valuable pharmacological tools for the supposed superior overall enhancing effect on histaminergic neurotransmission failed to appear hitherto.

Decreased brain histamine content in hypocretin/orexin receptor-2 mutated narcoleptic dogs

A growing amount of evidence suggests that a deficiency in hypocretin/orexin neurotransmission is critically involved in animal and human forms of narcolepsy. Since hypocretin-containing neurons innervate and excite histaminergic tuberomammillary neurons, altered histaminergic neurotransmission may also be involved in narcolepsy. We found a significant decrease in histamine content in the cortex and thalamus, two structures important for histamine-mediated cortical arousal, in Hcrtr-2 mutated narcoleptic Dobermans. In contrast, dopamine and norepinephrine contents in these structures were elevated in narcoleptic animals, a finding consistent with our hypothesis of altered catecholaminergic transmission in these animals. Considering the fact that histamine promotes wakefulness, decreases in histaminergic neurotransmission may also account for the sleep abnormalities in hypocretin-deficient narcolepsy.

Histamine N-methyltransferase regulates histamine-induced phosphoinositide hydrolysis in guinea pig cerebellum

We report here that the dose-response curve of the histamine-stimulated phosphoinositide hydrolysis in the guinea pig cerebellar slices was shifted to the left when the slices were pretreated with SKF 91488 (100 μM), a specific inhibitor of histamine N-methyltransferase (HMT). In contrast, the pretreatment of the cerebellar slices with aminoguanidine (100 μM–1 mM), an inhibitor of diamine oxidase, had no effect on histamine-induced phosphoinositide hydrolysis. HMT mRNA was expressed abundantly in cerebellum, especially in Purkinje cells. These observations suggest that HMT regulates histaminergic neurotransmission in guinea pig cerebellum more predominantly than diamine oxidase in histamine degradation.

Histamine H 1 receptors in patients with Alzheimer’s disease assessed by positron emission tomography

Cerebral histamine H 1 receptor binding was measured in vivo in 11 normal subjects (six young and five old) and 10 patients with Alzheimer’s disease by positron emission tomography and [ 11C]doxepin, a radioligand for H 1 receptors. The parametric images describing the tracer kinetics were generated by either compartmental or graphical analysis, and were examined statistically on region-of-interest and voxel-by-voxel bases. The binding potential of H 1 receptors showed a significant decrease particularly in the frontal and temporal areas of the Alzheimer’s disease brain compared to the old, normal subjects. In addition, the receptor binding correlated closely to the severity of Alzheimer’s disease assessed by the Mini-Mental State Examination score within several brain areas. The ratio of K1 values between the brain areas and the cerebellum was used as a relative measure of regional cerebral blood flow which decreased in the frontal and temporal areas of the Alzheimer’s disease brain. However, the difference in the binding potential (total concentration of receptor/equilibrium dissociation constant) between the Alzheimer’s disease patients and the old, normal subjects was greater than that in the cerebral blood flow, and the rate of decrease in the binding potential with the progression of Alzheimer’s disease was greater than the rate of decrease in the cerebral blood flow. This study reveals the predominant disruption of the histaminergic neurotransmission in the neurodegenerative processes of Alzheimer’s disease. This study suggests that the decline of the histamine receptor binding might play a substantial role in the cognitive deficits of Alzheimer’s disease patients.

Differential sensitivity of the caudal and rostral nucleus accumbens to the rewarding effects of a H1-histaminergic receptor blocker as measured with place-preference and self-stimulation behavior

A recent series of studies in rats has demonstrated positively reinforcing and memory enhancing effects following lesions of the nucleus tuberomammillaris, which is the only known source of neuronal histamine. The aim of the present experiments was to assess whether inhibition of histaminergic neurotransmission in the ventral striatum has positively reinforcing effects. In Experiment 1 rats with chronically-implanted cannulae were injected with the H1 receptor blocker d-(+)-chlorpheniramine at doses of 0.1, 1.0 and 10.0 μg into the rostral or caudal parts of the nucleus accumbens, a brain region known to be involved in reward-related processes. Immediately after the treatment the animals were placed into one of four restricted quadrants of a circular open field (closed corral) for a single conditioning trial. During the drug-free test for conditioned place preference, when a choice among the four quadrants was provided, those rats injected with 10.0 μg chlorpheniramine in the caudal nucleus accumbens spent more time in the treatment corral, indicative of a positively rewarding drug action. In Experiment 2 the question was posed whether injection of chlorpheniramine into the nucleus accumbens influences electrical self-stimulation of the lateral hypothalamus. For this purpose rats were chronically implanted with two bipolar electrodes aimed at the lateral-hypothalami and with two additional guide cannulae aimed either at the rostral or caudal nucleus accumbens. After having established reliable self-stimulation behavior at one of the two electrode sites the animals were allowed to self-stimulate for one hour (baseline). Then they were unilaterally injected with 10.0 μg chlorpheniramine or vehicle and allowed to self-stimulate for another hour (test). On the next day the same procedure took place, except for the difference that the animals received an injection aimed at the hemisphere not treated so far. Animals treated with chlorpheniramine in the caudal and in the rostral nucleus accumbens displayed higher rates of ipsihemispheric self-stimulation behavior. Moreover, the animals treated with the H1 receptor blocker in the caudal nucleus accumbens displayed higher rates of ipsihemispheric self-stimulation than those having received an injection in the rostral pole. Upon completion of this part of the experiment all animals received an additional intraperitoneal treatment with chlorpheniramine (20 mg/kg) or vehicle, respectively, and were tested in the same way described above. This treatment also resulted in an amplification of intracranial self-stimulation behavior. These results support the hypothesis that histaminergic neurotransmission is involved in the inhibitory control of a central system subserving reward-related processes. The present data also further highlight the nucleus accumbens as functionally heterogenous along its rostrocaudal axis, with the caudal-shell subregion being more sensitive to antihistaminic induced reward than the rostral entity.

Major Changes in the Brain Histamine System of the Ground SquirrelCitellus lateralisduring Hibernation

Hibernation in mammals such as the rodent hibernator Citellus lateralis is a physiological state in which CNS activity is endogenously maintained at a very low, but functionally responsive, level. The neurotransmitter histamine is involved in the regulation of diurnal rhythms and body temperature in nonhibernators and, therefore, could likely play an important role in maintaining the hibernating state. In this study, we show that histamine neuronal systems undergo major changes during hibernation that are consistent with such a role. Immunohistochemical mapping of histaminergic fibers in the brains of hibernating and nonhibernating golden-mantled ground squirrels (C. lateralis) showed a clear increase in fiber density during the hibernating state. The tissue levels of histamine and its first metabolite tele-methylhistamine were also elevated throughout the brain of hibernating animals, suggesting an increase in histamine turnover during hibernation, which occurs without an increase in histidine decarboxylase mRNA expression. This hibernation-related apparent augmentation of histaminergic neurotransmission was particularly evident in the hypothalamus and hippocampus, areas of importance to the control of the hibernating state, in which tele-methylhistamine levels were increased more than threefold. These changes in the histamine neuronal system differ from those reported for the metabolic pattern in other monoaminergic systems during hibernation, which generally indicate a decrease in turnover. Our results suggest that the influence of histamine neuronal systems may be important in controlling CNS activity during hibernation.

Histamine H2 Receptor Antagonists in Schizophrenia

The serendipitous observation that famotidine, a competitive histamine H2 receptor antagonist, administered as the sole medication to a patient with schizophrenia and coincidental peptic ulcer disease, was associated with a dramatic resolution of positive and negative symptoms, has stimulated the examination of a possible role for histamine in the pathophysiology of schizophrenia. It has been found that the terminal projections of histaminergic neurons originating in the posterior hypothalamus include regions implicated prominently in the pathophysiology of schizophrenia. Elevations of levels of histamine and its principal methylated metabolite in the CSF of patients with schizophrenia have been reported, and selective alterations of histamine receptor subtypes in autopsied brains from patients who had had schizophrenia support the possible existence of pathologically altered histaminergic neurotransmission.

Regulation of hypothalamic preprogrowth hormone-releasing factor messenger ribonucleic acid expression in food-deprived rats: a role for histaminergic neurotransmission

Regulation of hypothalamic preprogrowth hormone-releasing factor messenger ribonucleic acid expression in food-deprived rats: a role for histaminergic neurotransmission