Postischemic regulation of central histamine receptors.

This study characterizes changes occurring in the central histaminergic system associated with ischemia-reperfusion pathology in the rat. Specifically, after a postocclusion time period of 48 h, we have analyzed histamine H(1) receptor mRNA expression, histamine H(2) receptor protein amount and binding densities, and histamine H(3) receptor mRNA expression and binding densities in brain regions that have been suggested to be selectively vulnerable to transient global ischemia, i.e. hippocampus, thalamus, caudate-putamen, and cerebral cortex. We found an increase in H(1) receptor mRNA expression in the caudate-putamen: given that ischemia reduces glucose uptake and H(1) receptor activation has been shown to decrease this effect, an increase of expression levels may result in mitigating tissue damage due to energy failure observed in ischemia. A decrease in H(2) receptor binding densities in the caudate-putamen was also observed; the ischemia-induced decrease in H(2) receptor protein was also detectable by Western blot analysis. This phenomenon may underlie the previously reported ischemia induced striatal dopamine release. H(3) receptor mRNA expression was increased in the caudate putamen of the postischemic brain but was decreased in the globus pallidus and the thalamus; in association with this, H(3) receptor binding densities were increased in the cortex, caudate-putamen, globus pallidus, and hippocampus. The upregulation of H(3) receptor ligand binding may be involved in the previously reported continuous neuronal histamine release. Our data suggest that central histamine receptor expression and ligand binding are altered in brain ischemia in distinct areas, and may participate in neuroprotection and/or ischemia-associated neuronal damage.

The histaminergic system in the brain: structural characteristics and changes in hibernation.

Histaminergic neurons in adult vertebrate brain are confined to the posterior hypothalamic area, where they are comprised of scattered groups of neurons referred to as the tuberomammillary nucleus. Histamine regulates hormonal functions, sleep, food intake, thermoregulation and locomotor activity, for example. In the zebrafish, Danio rerio, histamine was detected only in the brain, where also the histamine synthesizing enzyme L-histidine decarboxylase (HDC) was expressed. It is possible that histamine has first evolved as a neurotransmitter in the central nervous system. We established sensitive quantitative in situ hybridization methods for histamine H(1) and H(2) receptors and HDC, to study the modulation of brain histaminergic system under pathophysiological conditions. A transient increase in H(1) receptor expression was seen in the dentate gyrus and striatum after a single injection of kainic acid, a glutamate analog. H(1) antagonists are known to increase duration of convulsions, and increased brain histamine is associated with reduced convulsions in animal models of epilepsy. No HDC mRNA was detected in brain vessels by in situ hybridization, which suggests lack of histamine synthesis by brain endothelial cells. This was verified by lack of HDC mRNA in a rat brain endothelial cell line, RBE4 cells. Both H(1) and H(2) receptor mRNA was found in this cell line, and the expression of both receptors was downregulated by dexamethasone. The findings are in agreement with the concept that histamine regulates blood-brain barrier permeability through H(1) and H(2) receptor mediated mechanisms. Hibernation is characterized by a drastic reduction of central functions. The activity of most transmitter systems is maintained at a very low level. Surprisingly, histamine levels and turnover were clearly elevated in hibernating ground squirrels, and the density of histamine-containing fibers was higher than in euthermic animals. It is possible that histamine actively maintains the low activity of other transmitters during the hibernation state.

Lack of histamine synthesis and down-regulation of H1 and H2 receptor mRNA levels by dexamethasone in cerebral endothelial cells.

The purpose of this work was to determine whether cerebral endothelial cells have the capacity to synthesize histamine or to express mRNA of receptors that specifically respond to available free histamine. The histamine concentrations and the expression of L-histidine decarboxylase (HDC) and histamine H1 and H2 receptor mRNA, both in adult rat brain and in cultured immortalized RBE4 cerebral endothelial cells, were investigated. In this study endothelial cells were devoid of any kind of detectable histamine production, both in vivo and in the immortalized RBE4 cells in culture. Both the immunostainings for histamine and the in situ hybridizations for HDC were negative, as well as histamine determinations by HPLC, indicating that endothelial cells do not possess the capacity to produce histamine. Also, glucocorticoid (dexamethasone) treatment failed to induce histamine production in the cultured cells. Although the cerebral endothelial cells lack histamine production, a nonsaturable uptake in RBE4 cells is demonstrated. The internalized histamine is detected both in the cytoplasm and in the nucleus, which could indicate a role for histamine as an intracellular messenger. Histamine H1 and H2 receptor mRNA was expressed in RBE4 cells, and glucocorticoid treatment down-regulated the mRNA levels of both H1 and H2 receptors. This mechanism may be involved in glucocorticoid-mediated effects on cerebrovascular permeability and brain edema.

Major changes in the brain histamine system of the ground squirrel Citellus lateralis during 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.

Postnatal expression of H1-receptor mRNA in the rat brain: correlation to L-histidine decarboxylase expression and local upregulation in limbic seizures.

Histamine is implicated in the regulation of brain functions through three distinct receptors. Endogenous histamine in the brain is derived from mast cells and neurons, but the importance of these two pools during early postnatal development is still unknown. The expression of histamine H1-receptor in the rat brain was examined using in situ hybridization during postnatal development and in adults. For comparison, the expression of L-histidine decarboxylase (HDC) in the two pools was revealed. H1-receptor was evenly expressed throughout the brain on the first postnatal days, but resembled the adult, uneven pattern already on postnatal day 5 (P5). HDC was expressed in both mast cells and tuberomammillary neurons from birth until P5, after which the mast cell expression was no more detectable. In adult rat brain, high or moderate levels of H1-receptor expression were found in the hippocampus, zona incerta, medial amygdaloid nucleus and reticular thalamic nucleus. In most areas of the adult brain the expression of H1-receptor mRNA correlates well with binding data and histaminergic innervation. A notable exception is the hypothalamus, with high fibre density but moderate or low H1-receptor expression. Systemic kainic acid administration induced increased expression of H1-receptor mRNA in the caudate-putamen and dentate gyrus, whereas no change was seen in the hippocampal subfields CA1-CA3 or in the entorhinal cortex 6 h after kainic acid injections. This significant increase supports the concept that histaminergic transmission, through H1-receptor, is involved in the regulation of seizure activity in the brain.

Neuronal histamine deficit in Alzheimer's disease.

Histamine is known to be a neurotransmitter in the brain, but it has not been clearly implicated in major diseases. All histaminergic neurons reside in the posterior hypothalamus and innervate most brain areas, which is compatible with the concept that histamine is involved in general central regulatory mechanisms. A sensitive high-performance liquid chromatographic fluorimetric method was used to measure histamine contents in post mortem Alzheimer brains and age-matched controls. The cellular storage sites and distribution of histaminergic nerve fibers were examined with a specific immunohistochemical method. The histamine content was significantly reduced in the hypothalamus (42% of control value), hippocampus (43%) and temporal cortex (53%) of Alzheimer brains. Differences in other cortical areas, putamen and substantia nigra were not significant. Histamine-containing nerve fibers were found in the hippocampus, parahippocampal gyrus and subiculum of both Alzheimer brains and controls. No histamine-containing mast cells were seen in these temporal structures. Histamine in the human temporal lobe is stored in nerve fibers originating from the posterior hypothalamus, and not in mast cells. Decrease in brain histamine may contribute to the cognitive decline in Alzheimer's disease directly or through the cholinergic system. Development of drugs that penetrate the blood brain barrier and increase histaminergic activity might be beneficial in Alzheimer's disease.