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In general, rats and mice have not been used in research on emesis because they do not vomit. However, emetogenic stimuli such as anticancer drugs, apomorphine, copper sulfate and rotation induced pica, a behavior characterized by eating nonfood substances such as kaolin, in rats. We also found that cisplatin induced pica in mice, but it was rather difficult to determine the exact kaolin consumption in this species. In this study, we prepared kaolin pellets mixed with carmine, a dye not absorbed in the gastrointestinal tract, and estimated kaolin consumption by determination of carmine excreted in feces. Cisplatin (5 mg/kg) caused a significant increase in kaolin consumption (saline: 0.15 +/- 0.08 g vs. cisplatin: 0.45 +/- 0.16 g) and pretreatment with the 5-HT3 receptor antagonist, ondansetron (2 mg/kg), suppressed the increased consumption (vehicle: 0.33 +/- 0.05 g vs. ondansetron: 0.13 +/- 0.04 g). These findings suggested that the exact kaolin consumption could be quantified by the determination of carmine in feces and that mice could be useful for studying emesis.

Using a microdialysis method and a new high performance liquid chromatography (HPLC)-fluorometric method for the detection of gamma-aminobutyric acid (GABA), we investigated the effect of thioperamide, an H3 receptor antagonist, on the GABA content in the dialysate from the anterior hypothalamic area of rats anesthetized with urethane. The addition of thioperamide to the perfusion fluid increased the release of GABA and histamine. Depleting neuronal histamine with alpha-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase, and the administration of immepip, an H3 agonist, had no effect on basal- and thioperamide-induced GABA release. In addition, an infusion of clobenpropit, the most specific H3 receptor antagonist available, did not alter the basal release of GABA. On the other hand, histamine release was decreased by immepip and increased by thioperamide and clobenpropit. Removing Ca2+ from the perfusion fluid did not alter the effect of thioperamide on the GABA release, whereas that on histamine release was abrogated. These results suggest that the effect of thioperamide on GABA release is not mediated by histamine H3 receptors and that thioperamide acts on the transporter to cause an efflux of GABA from neurons and/or glia. Thioperamide is a popular H3 receptor antagonist which has been used applied to many studies. However, results using this compound should be interpreted in consideration of its effects on GABA release.

The effects of diphenhydramine, domperidone, ondansetron, and diphenidol on cisplatin-induced pica (i.e., kaolin ingestion) in rats as the measure analogous to emesis in other species were examined. Ondansetron (2 mg/kg) and diphenidol (30 mg/kg) inhibited kaolin intake induced by cisplatin (10 mg/kg), but diphenhydramine and domperidone did not. Diphenhydramine and diphenidol have been shown to inhibit kaolin intake induced by double rotation, while domperidone and ondansetron did not, and kaolin intake induced by apomorphine was inhibited by domperidone and diphenidol, but not by diphenhydramine or ondansetron. These observations, together with the present findings, suggest that the emetic pathways through the inner ear (double rotation), chemoreceptor trigger zone (apomorphine) and visceral afferent (cisplatin), are pharmacologically independent and are mediated by histamine H1 receptors, dopamine D2 receptors and serotonin 5-HT3 receptors, respectively. It is conceivable that diphenidol may inhibit the emetic center itself, although the receptor on which it acts is not known.

The effects of diphenhydramine, domperidone, ondansetron, and diphenidol on motion- and apomorphine-induced pica (i.e., kaolin ingestion) in rats as the measure analogous to emesis in other species were examined. Diphenhydramine (10 and 20 mg/kg) and diphenidol (30 mg/kg) inhibited kaolin intake induced by 60-min double rotation, while domperidone and ondansetron did not. Kaolin intake induced by apomorphine (10 mg/kg) was inhibited by domperidone (2 mg/kg) and diphenidol (30 mg/kg), but not by diphenhydramine or ondansetron. These findings suggest that the emetic pathways through the inner ear (double rotation) and the chemoreceptor trigger zone (apomorphine) are pharmacologically independent and are mediated by histamine H1 receptors and dopamine D2 receptors, respectively. Diphenidol may inhibit a common locus of emesis.

A clone encoding a part of rat histamine N-tele-methyltransferase gene of 11 kb was isolated. The clone contained 4 exons, encoding from 191 to the 3' end of cDNA. The last exon was 692 bases long and specified more than half of the HMT cDNA. A comparison of the sequences of rat and human cDNAs shows that more than one-third of the human 3' untranslated region does not correspond to the rat counterpart, but a homology was found between this region of human cDNA and the 3' franking region of the rat gene. It was found that an exon was interrupted at 4 residues after a glycine residue, which putatively corresponds to the conserved residue among methyltransferases.

The purpose of this study was to examine the effects of intracerebroventricular (i.c.v.) administration of N-acetylhistamine on rectal temperature, histamine level, histidine decarboxylase (HDC) activity, and the turnover rate of monoamines in mice. More than 60 micrograms of N-acetylhistamine induced hypothermia. The maximum effect of hypothermia was observed 20 min after administration of N-acetylhistamine (60-120 micrograms/mouse). A significant drop in rectal temperature of 3 degrees C was induced by 120 micrograms of N-acetylhistamine. Concurrent with the appearance of hypothermia, the histamine levels were increased. However, both histamine H1 and H2 antagonists did not prevent hypothermia. The i.c.v. administration of N-acetylhistamine inhibited HDC activity, but had no effect on the turnover rates of monoamines. These data confirmed that endogenous N-acetylhistamine may be a metabolite which lacks significant physiological roles, and demonstrated that exogenous N-acetylhistamine is not a good pharmacological tool for the study of the functions of the brain histaminergic system in mammals.

Alpha-fluoromethylhistidine (FMH), a histamine synthesis inhibitor, was infused into the lateral cerebral ventricle of male Long-Evans rats for 7 days at a dose of 60 mcg/day. During this period animals were housed in metabolic cages; water and food consumption were measured and urine samples were collected. FMH-treated rats ate significantly more than controls and had a significantly greater weight increase. Concomitantly, sodium and potassium excretion increased. On the seventh day, rats were injected i.p. with 6.67 ml/kg of either 5.8% NaCl or physiological saline. Animals were decapitated 1 h after injection and plasma vasopressin, corticosterone and posterior pituitary vasopressin levels were determined by radioimmunoassay. NaCl loading significantly increased plasma vasopressin in control rats but not in rats pretreated with FMH. FMH alone had no effect. There were no significant changes in pituitary vasopressin or plasma corticosterone. These results clearly suggest an inhibitory role for the histaminergic system in the regulation of food intake. They also agree with, although not proving, the stimulatory control of vasopressin release by the histaminergic system in rat brain.

The effect of intracerebroventricular (icv) administration of lipopolysaccharide on histidine decarboxylase activity and histamine content in the hypothalamus were investigated in male mice of ddY strain in vivo. Two-fold increase in histidine decarboxylase activity (HDC) was observed 4 h after administration of 50 mcg lipopolysaccharide, and HDC activity returned to the basal level within 12 h after injection. Furthermore, histamine contents showed a slight decrease at 1 and 2 h and a mild increase at 12 h after administration. However, changes in histamine content were not statistically significant. These results suggest that the increase of HDC activity in the hypothalamus by lipopolysaccharide may be involved in the central neuroimmune responses.

Rats maintained on a thiamine-deficient diet for 30 days showed mouse-killing aggression (muricide). Once the muricide tendency appeared, it remained during the entire experimental period, even after subsequent administration of thiamine hydrochloride for 30 days. The effect of alpha-fluoromethylhistidine (FMH) on muricide in this animal model was examined, and histamine and noradrenaline levels in several brain regions were measured. One hour after i.p. injection of 200 mg/kg of FMH, muricide was completely abolished. Significant decrease in histamine levels was found in the hypothalamus, thalamus, amygdala, striatum and pituitary of muricidal rats. Thus, the central histaminergic neuron system may be involved in the suppressive mechanism of muricide. On the other hand, it is noteworthy that the noradrenaline level was significantly decreased only in the hypothalamus. In conclusion, it seems likely that the suppression of muricide induced by FMH was attributable to both inhibition of the histaminergic system and activation of the noradrenergic system.

One hour after the intraperitoneal (i.p.) injection of FMH (200 mg/kg), locomotor activity and rearing were statistically reduced, by 3 hours later, only the locomotor activity was reduced in rats. The i.p. injection of FMH (100 and 200 mg/kg) had no effects on motor incoordination, blood pressure, heart rate and tetrabenazine-induced ptosis in rats. One and 3 hours after FMH injection, the histamine levels significantly decreased in the hypothalamus, cortex and thalamus, slightly in the olfactory bulb, amygdala, pons-medulla oblongata and midbrain, but very little in the striatum, hippocampus, cerebellum and pituitary. On the other hand, noradrenaline and dopamine levels were not affected in most of the regional parts, although in the cortex and midbrain, the dopamine levels were slightly reduced 1 hour after FMH (100 and 200 mg/kg). These data showed that central histamine may play an important role in the locomotor activity of rats.

The effects of cholinergic agents on the K(+)-evoked release of endogenous histamine from hypothalamic slices of rats were examined by a superfusion method in vitro. Acetylcholine and carbamylcholine significantly inhibited K(+)-evoked release of histamine from the slices, and the effect of acetylcholine was antagonized by the muscarinic antagonist atropine. On the other hand, nicotine significantly enhanced the K(+)-evoked release and its effect was antagonized by the nicotinic antagonist hexamethonium. The effects of carbamylcholine and nicotine on histamine release from slices of whole hypothalamus and from slices of the anterior hypothalamic region, which do not contain cell bodies of the histaminergic neurons, were the same. Thus, the K(+)-evoked release of endogenous histamine from histaminergic fibers in the hypothalamic slices was inhibited by muscarinic agents and enhanced by nicotinic agents. These results suggest that muscarinic and nicotinic receptors exert antagonistic effects on the release of hypothalamic histamine from in vitro slice preparations. The cholinergic receptors modulating histamine release might be located presynaptically on the histaminergic terminals.

The concentration of histamine (HA) has been determined by high-performance liquid chromatography (HPLC) with fluorometric detection in 21 different regions of brains from patients with senile dementia of the Alzheimer type (SDAT) and subjects (CB) whose causes of death were not related to neuropsychiatric, neurological and/or neurodegenerative diseases. The highest levels of HA in the central nervous system (CNS) of both control (CB) and SDAT samples were found in the posterior hypothalamus (CB = 3.13 +/- 0.63 pmol/mg; SDAT = 7.75 +/- 1.43 pmol/mg, p less than 0.005), where the HA neurons are located, and in the anterior hypothalamus (CB = 1.77 +/- 0.33 pmol/mg; SDAT = 2.82 +/- 0.45 pmol/mg, p less than 0.005). The lowest HA levels were detected in the cerebellum (CB = 0.12 +/- 0.04 pmol/mg; SDAT = 0.24 +/- 0.09 pmol/mg, p less than 0.01) and medulla oblongata. HA levels were significantly higher in SDAT than in CB in the following areas: motor cortex (Brodmann's area 4) (A4), premotor cortex (A6), postcentral gyrus (A1,2), posterior parietal cortex (A5,7), superior temporal gyrus (A41,42), temporal pole (A38), primary and secondary visual cortices (A17,18), anterior and posterior regions of the hypothalamus, putamen, caudate nucleus, nucleus accumbens, thalamus, hippocampus, pons, medulla oblongata and cerebellum. No changes were seen in globus pallidus and corpus callosum. Since the origin of HA in the brain is dependent upon three main compartments (neuronal, mast cell, vascular smooth muscle), with approximately 60-80% of the total HA belonging to the neuronal pool, on the basis of neurochemical data we postulate that the increase in the levels of HA in SDAT might account for or be associated with alterations in neuroendocrine, cognitive, neurovascular and sleep-wakefulness functions.