Eiko Sakurai

Mice lacking histidine decarboxylase exhibit abnormal mast cells

Histidine decarboxylase (HDC) synthesizes histamine from histidine in mammals. To evaluate the role of histamine, we generated HDC‐deficient mice using a gene targeting method. The mice showed a histamine deficiency and lacked histamine‐synthesizing activity from histidine. These HDC‐deficient mice are viable and fertile but exhibit a decrease in the numbers of mast cells while the remaining mast cells show an altered morphology and reduced granular content. The amounts of mast cell granular proteases were tremendously reduced. The HDC‐deficient mice provide a unique and promising model for studying the role of histamine in a broad range of normal and disease processes.

Behavioural characterization and amounts of brain monoamines and their metabolites in mice lacking histamine H1 receptors

Behavioural assessments were made of mutant mice lacking histamine H1 receptors to reveal the function of H1 receptors in the behaviour of mice. Exploratory behaviour of mice in a new environment was examined to discover whether the absence of H1 receptors in mice affects actions relating to their emotions. The H1 receptor-deficient mice showed a significant decrease in ambulation in an open field and on an activity wheel. Cognitive functions and anxiety were examined using passive avoidance response test and the elevated plus-maze test, respectively. The passive avoidance test did not show any change in latency. The elevated plus-maze test revealed that the transfer latency of the mutant mice was significantly prolonged, indicating that H1 receptors are partly associated with the control of anxiety. Aggressive behaviour was examined by a resident-intruder aggression test. When confronted with an intruder, the mutant mice attacked the intruder significantly slower and less frequently than did wild-type mice after a six-month isolation period. A formalin test and a forced swimming test were used to evaluate the nociceptive response and depressive or despairing state, respectively, of both groups. The mutant mice showed a significant decrease of nociceptive response in the late phase without affecting the early phase. There was no significant difference in the forced swimming test between the two groups. The brain content of monoamines and their metabolites was measured in the H1 receptor null and wild-type mice. The turnover rate of 5-hydroxytryptamine defined by the ratio of 5-hydroxyindoleacetic acid and 5-hydroxytryptamine was significantly increased in the cerebral cortex and hippocampus of H1 receptor null mice. These results support the previous pharmacological findings that histamine modulates various neurophysiological functions such as locomotor activity, emotion, memory and learning, nociception and aggressive behaviour through H1 receptors.

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.

Effects of thioperamide, a histamine H3 antagonist, on the step-through passive avoidance response and histidine decarboxylase activity in senescence-accelerated mice

The effect of thioperamide, a histamine H3 receptor antagonist, on learning and memory was studied in the senescence-accelerated mice-prone strain (SAM-P/8) and normal-rate aging strain (SAM-R/1). In a passive avoidance test, SAM-P/8 mice of 12 months showed significant impairment of learning and memory compared with SAM-R/1 mice of the same age. Thioperamide significantly improved the response latency in SAM-P/8 mice when injected intraperitoneally at a dose of 15 mg/kg. The histidine decarboxylase (HDC) activity in the forebrain was significantly lower in SAM-P/8 mice than in SAM-R/1 mice. Thioperamide administration significantly potentiated HDC activity in the forebrain of SAM-P/8 mice as well as improving learning and memory. These results suggest that central histaminergic neurons may be involved in learning and memory impairment of SAM-P/8 mice, although other possibilities are not ruled out.

Selective cognitive dysfunction in mice lacking histamine H1 and H2 receptors.

Previous pharmacological experiments provide conflicting findings that describe both facilitatory and inhibitory effects of neuronal histamine on learning and memory. Here, we examined learning and memory and synaptic plasticity in mice with a null mutation of gene coding histamine H1 or H2 receptor in order to clarify the role of these receptors in learning and memory processes. Learning and memory were evaluated by several behavioral tasks including object recognition, Barnes maze and fear conditioning. These behavioral tasks are highly dependent on the function of prefrontal cortex, hippocampus or amygdala. Object recognition and Barnes maze performance were significantly impaired in both H1 receptor gene knockout (H1KO) and H2 receptor gene knockout (H2KO) mice when compared to the respective wild-type (WT) mice. Conversely, both H1KO and H2KO mice showed better auditory and contextual freezing acquisition than their respective WT mice. Furthermore, we also examined long-term potentiation (LTP) in the CA1 area of hippocampus in H1KO and H2KO mice and their respective WT mice. LTP in the CA1 area of hippocampus was significantly reduced in both H1KO and H2KO mice when compared with their respective WT mice. In conclusion, our results demonstrate that both H1 and H2 receptors are involved in learning and memory processes for which the frontal cortex, amygdala and hippocampus interact.

Increased methamphetamine‐induced locomotor activity and behavioral sensitization in histamine‐deficient mice

We have recently suggested that the brain histamine has an inhibitory role on the behavioral effects of methamphetamine by pharmacological studies. In this study, we used the histidine decarboxylase gene knockout mice and measured the spontaneous locomotor activity, the changes of locomotion by single and repeated administrations of methamphetamine, and the contents of brain monoamines and amino acids at 1 h after a single administration of methamphetamine. In the histidine decarboxylase gene knockout mice, spontaneous locomotor activity during the dark period was significantly lower than in the wild‐type mice. Interestingly, methamphetamine‐induced locomotor hyperactivity and behavioral sensitization were facilitated more in the histidine decarboxylase gene knockout mice. In the neurochemical study, noradrenaline and O‐phosphoserine were decreased in the midbrain of the saline‐treated histidine decarboxylase gene knockout mice. On the other hand, single administration of methamphetamine decreased GABA content of the midbrain of the wild‐type mice, but did not alter that of histidine decarboxylase gene knockout mice. These results suggest that the histamine neuron system plays a role as an awakening amine in concert with the noradrenaline neuron system, whereas it has an inhibitory role on the behavioral effects of methamphetamine through the interaction with the GABAergic neuron system.

Plasma extravasation induced by dietary supplemented histamine in histamine‐free mice

Histidine decarboxylase (HDC) synthesizes endogenous histamine from histidine in mammals. To evaluate the role of histamine in skin allergic reaction, we used HDC gene knockout mice lacking histamine. No plasma extravasation reaction was observed in HDC(–/–) mice after passive cutaneous anaphylaxis (PCA) test. Compound 48/80, a mast cell granule depletor, produced plasma extravasation inHDC(+/+) mice but no extravasation in HDC(–/–) mice. Interestingly, orally administered histamine was distributed in the skin in HDC(–/–) mice and in these histamine‐supplemented mice the plasma extravasation reaction was observed after the injection of compound 48/80 and the PCA test. Cultured bone marrow‐derived mast cells of HDC(–/–) mice took up histamine from the histamine‐supplemented medium into the secretory granules. The absorbed histamine was released in response to the same antigen and antibody combination used as in PCA test. In contrast to the immediate‐type response, the delayed‐type hypersensitive response, observed as a thickening of the ear skin after trinitrochlorobenzene challenge (following sensitization), showed no differences between HDC(+/+) and HDC(–/–) mice. Therefore, among the allergic skin reactions, histamine is revealed to be an important mediator especially for the plasma extravasation in an immediate‐type allergy model.

Clobenpropit (VUF-9153), a new histamine H3 receptor antagonist, inhibits electrically induced convulsions in mice

The effect of clobenpropit (VUF-9153), a new histamine H3 receptor antagonist, on electrically induced convulsions was studied in mice. Clobenpropit significantly and dose dependently decreased the duration of each convulsive phase. Its anticonvulsant effects were prevented by pretreatment with (R)-alpha-methylhistamine and imetit (VUF-8325), histamine H3 receptor agonists. These findings suggest that the effect of clobenpropit on electrically induced convulsions is due to an increase in endogenous histamine release in the brain, which is consistent with biochemical results that clobenpropit increased brain histidine decarboxylase activity dose dependently. The anticonvulsive effect of clobenpropit was antagonized by mepyramine, a histamine H1 receptor antagonist, but not by zolantidine, a histamine H2 receptor antagonist, indicating that histamine released by the anticonvulsant effect of clobenpropit interacts with histamine H1 receptors of postsynaptic neurons. The present findings of the effect of clobenpropit on electrically induced convulsions are fully consistent with those of thioperamide as described previously (Yokoyama et al., 1993, Eur. J. Pharmacol. 234, 129), supporting the hypothesis that the central histaminergic neuron system is involved in the inhibition of seizures.

Chemical kindling induced by pentylenetetrazol in histamine H1 receptor gene knockout mice (H1KO), histidine decarboxylase-deficient mice (HDC−/−) and mast cell-deficient W/Wv mice

The role of brain histamine on seizure development of pentylenetetrazol (PTZ)-induced kindling was examined in H(1)-receptor gene knockout (H(1)KO), histidine decarboxylase-deficient (HDC(-/-)) and mast cell-deficient (W/W(v)) mice. All H(1)KO, HDC(-/-) and W/W(v) mice had accelerated seizure development of PTZ-induced kindling when compared to their respective wild-type mice. The daily PTZ-kindling increased histamine content in the cortex and diencephalon of H(1)KO mice, whereas the histamine content in the diencephalon of W/W(v) mice was decreased. The present study indicates that histamine plays a suppressive role in seizure development through H(1)-receptors.

Ontogenetic development of histamine receptor subtypes in rat brain demonstrated by quantitative autoradiography

The postnatal ontogenetic development of the histamine receptor subtypes was studied in rat brain by quantitative receptor autoradiography with highly sensitive imaging plates. H1 receptor binding sites labeled with [3H]pyrilamine were detected on postnatal day 2 (P2) and increased very slowly until P9, and then rapidly reaching the adult levels in the hypothalamus, hippocampus, and amygdala by P16. The densities of H1 receptor binding sites in the cortex, striatum, thalamus, and substantia nigra were relatively low during development. H3 receptor binding sites labeled with [3H](R) alpha-methylhistamine were not detectable until P9. On P9, their density was higher in the substantia nigra than in other regions. Subsequently, H3 receptor binding increased, reaching the adult levels in the substantia nigra on P16 and in the other regions on P23. The histamine concentration was initially very high, but decreased to the adult level by P16. On the contrary, the activity of L-histidine decarboxylase of whole brain tissue was low on P5, and increased markedly from P16 to P23, to the adult level on P30. Administration of (S) alpha-fluoromethylhistidine (FMH), a specific inhibitor of L-histidine decarboxylase (HDC), significantly decreased both the HDC activity and histamine concentration during postnatal development. FMH treatment did not change H1 receptor binding in any brain region, but significantly increased H3 receptors in the substantia nigra and striatum on P23. Unilateral injection of 6-hydroxydopamine into the striatum on P2 resulted in up-regulation of H3 receptor binding sites in the dorsomedial (11%) and dorsolateral (18%) regions of the striatum and substantia nigra (31%) on P23, but no change in the H3 receptor density in the nucleus accumbens or frontal cortex on P11 and P23. These results demonstrate that the developmental patterns of H1 and H3 receptors are heterogeneous and independent of each other. There are marked mismatches of presynaptic and postsynaptic markers of the histaminergic neuron system as in other aminergic systems.