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Cancer chemotherapy often induces gastrointestinal symptoms such as anorexia, nausea, and vomiting. Antiemetic agents are effective in inhibiting nausea and vomiting, but patients still experience anorexia. We previously reported that chemotherapeutic agent-induced anorexia is associated with an increase of inflammatory cytokines. Other studies also reported that antagonism of the histamine H4 receptor is anti-inflammatory. In this study, we investigated the involvement of the H4 receptor in the development of chemotherapy-induced anorexia in mice. Cisplatin-induced anorexia occurred within 24 h of its administration and continued for 3 days. The early phase (day 1), but not the delayed phase (days 2 and 3), of anorexia was inhibited by the daily injection of a 5-HT3 receptor antagonist (granisetron). However, a corticosteroid (dexamethasone) or selective H4 receptor antagonist (JNJ7777120) abolished the delayed phases of anorexia. Cisplatin significantly increased TNF-α mRNA expression in the hypothalamus and spleen, and the period of expression increase paralleled the onset period of anorexia. In addition, pretreatment with JNJ7777120 completely inhibited the increased expression. These results suggest that TNF-α mRNA expression via H4 receptors may contribute to the development of cisplatin-induced anorexia, and that H4 receptor antagonists are potentially useful treatments.

Modafinil is a drug used to treat hypersomnolence of narcolepsy. We previously reported that modafinil increases hypothalamic histamine release in rats but did not increase locomotor activity in histamine-depleted mice, suggesting that modafinil-induced locomotor activity involves the histaminergic system. Modafinil is also thought to express its effect through the orexinergic neurons, and orexin increases hypothalamic histamine release. These findings led us to investigate whether modafinil activates the histaminergic system via the orexinergic system. In the present study, we performed in vivo microdialysis and c-Fos immunohistochemistry to investigate whether the orexinergic system mediates the activation of the histaminergic system by modafinil using orexin neuron-deficient mice. Two hours after the injection, modafinil (150 mg/kg) caused a significant increase of histamine release compared to the basal release in wild type mice. However, modafinil had no effect on the histamine release in orexin neuron-deficient mice. By immunohistochemical study, we found that there was no neuronal activation in the tuberomammillary nucleus where the cell bodies of the histaminergic neurons exclusively exist in orexin neuron-deficient mice. These findings indicate that modafinil-induced increment of histamine release requires intact orexinergic neurons.

Schizophrenia is a chronic mental disorder and patients with this disease show positive and negative symptoms, cognitive dysfunction, and deficits in the processing of emotion. From previous studies, dopaminergic neurons are believed to be related to schizophrenic symptoms. Dysbindin (DTNBP1: dystrobrevin binding protein 1) gene is a susceptibility gene for schizophrenia, but the involvement of this gene in the dopaminergic tone remains unknown. In this paper, we studied regional contents of dopamine and its metabolite in the Sandy (Sdy) mouse which expresses no dysbindin protein. The brains of Sdy and wild-type (WT) mice were dissected into ten regions and dopamine (DA) and homovanillic acid (HVA) in each region were determined. DA contents were significantly lower in the cortex, hippocampus, and hypothalamus of Sdy mice than WT mice, while HVA contents showed no differences between the strains. Western blot analysis revealed there were no differences in the amount of tyrosine hydroxylase (TH) in the midbrain (MB) of both strains. The ratios of DA to HVA, which is an index of DA turnover, were higher in the cortex and the hippocampus, but not in the hypothalamus. These data demonstrate that DA turnover in the specific regions of the brain of the Sdy mouse was increased, and the Sdy mouse is a possible useful candidate animal for studying the pathogenic mechanism of schizophrenia.

Previously, we observed that in rats, olfactory stimulation with scent of grapefruit oil (SGFO) elevates the activities of sympathetic nerves. SGFO also suppresses gastric vagal (parasympathetic) nerve activity (GVNA), increases the plasma glycerol concentration, blood pressure (BP) and body temperature, and reduces appetite. In contrast, olfactory stimulation with scent of lavender oil (SLVO) has opposite effects in rats. Here, we show that in mice, olfactory stimulation with SGFO elevated activities of sympathetic nerves innervating the kidney, adrenal gland and brown adipose tissue as well as increasing BP and suppressing GVNA, whereas olfactory stimulation with SLVO decreased these sympathetic nerve activities and BP, and elevated GVNA. Electrolytic lesions of the mouse hypothalamic suprachiasmatic nucleus (SCN) eliminated changes in renal sympathetic nerve activity (RSNA), BP and GVNA induced by either SGFO or SLVO. Furthermore, SGFO-induced elevations in RSNA and BP and the SLVO-induced GVNA increase were not observed in Cryptochrome (Cry)-deficient mice, which harbor mutations in both cry1 and cry2 and lack normal circadian rhythms. These findings suggest that SGFO and SLVO affect autonomic neurotransmission and BP via the SCN in mice. Moreover, the molecular clock mechanism in the SCN, which involves the cry1 and cry2 genes, is partially involved in mediating these autonomic and cardiovascular actions of SGFO and SLVO.

The neuropeptides orexin-A and -B have been reported to be appetite-stimulating peptides, but they are also known as important factors that control arousal state. We studied the effects of orexin-A and -B on the hypothalamic histamine release using in vivo microdialysis. A significant and sustained increase in histamine release was observed by intracerebroventricular injection of 1 nmol of orexin-A, but not by the same dose of orexin-B. An increased dose of orexin-B to 5 nmol facilitated histamine release, although this effect was much less potent than orexin-A. These findings suggest that both of the orexins play important roles in the regulation of waking through the activation of histaminergic system.

Histamine is found in nerve cell bodies of the tuberomammillary nucleus in mammalian brain. This nucleus is prominent in human brain. Samples of human cerebelli obtained from neurosurgical operations were examined for the presence of histamine-containing nerve fibers. In all samples, a moderately dense network of histamine-immunoreactive fibers was seen in the molecular layer. These fibers ran parallel to the Purkinje cell layer after traversing it perpendicularly. Numerous fibers were also seen in the granular cell layer. The results suggest that the human cerebellar cortex receives a direct input from histamine-synthesizing hypothalamic neurons, as no other histamine-containing neurons have been found in human brain.

We studied the extracellular concentration of glutamate and taurine in the frontal cortex of freely-moving pentylenetetrazole (PTZ) kindled rats using an in vivo microdialysis. A significant and sustained increase in the glutamate level was observed in the kindled rats, in contrast, a slight and delayed increase was observed in the non-kindled rats when the same grade seizure was induced by PTZ. The convulsive dose of PTZ administration caused a decrease in taurine levels in the controls, however, no significant changes were found in the kindled rats.

The diurnal variations of pineal indoles in New-Zealand Black (NZB) mice and Wistar rats were determined by HPLC fluorometry. Pineal N-acetylserotonin (NAc5HT) in NZB mice showed a marked diurnal variation, but no melatonin (MLT) was detected at any time of day or night. The night-time increases of NAc5HT in NZB mice and MLT in Wistar rats were delayed about one hour in animals kept under illumination of high intensity (2000 lux) during the light period (12 h) compared with those in animals kept under illumination of low intensity (10 lux). These results suggest that the intensity of illumination during the light period affects the diurnal rhythms of pineal indoles in experimental animals.

Modafinil, (RS)-2-(Diphenylmethylsulfinyl)acetamide, is a well known wake promoting drug used for the treatment of narcolepsy. We investigated the effect of modafinil on the hypothalamic histamine release in the anesthetized rat using in vivo microdialysis. Modafinil (150 mg/kg, i.p.) increased histamine release by 150% of the basal release. The intracerebroventricular (i.c.v.) injection of modafinil (1 nmol) also increased histamine release, however, when modafinil (1 nmol) was injected directly into the tuberomammillary nucleus, a limited region where cell bodies of the histaminergic neurons are located, histamine release was not altered. These observations suggest that modafinil may promote waking via the activation of the histaminergic system, although it does not appear to be a direct pharmacological target of modafinil.

We previously reported that cells other than mast cells or neurons could synthesize histamine in response to lipopolysaccharide (LPS) or interleukin 1beta in the rat brain. To identify the responsible cells, we examined histidine decarboxylase (HDC) activity and the expression of HDC mRNA in GMI 6-3 mouse microglial cells. Both the activity and mRNA for HDC in GMI 6-3 cells were induced by LPS treatment, and the induction was sensitive to calmodulin-dependent kinase II inhibitor, KN62. These findings indicate that microglia is a third cell type producing histamine in the brain.

We studied the effect of ethylcholine mustard aziridinium ion (AF64A), a cholinergic neurotoxin, on the footshock stimulation (FS)-induced excitation of the locus coeruleus (LC) neurons in rats. The FS-evoked LC excitation was significantly reduced in AF64A-treated rats, in comparison with normal rats. In particular, the early component of LC excitation was less pronounced. The number of choline acetyltransferase immunoreactive neurons in the septal complex was significantly lower than those in normal rats, except for in the ventral subgroup. These findings suggest that the cholinergic neuron system is involved in the early component of LC excitation in rats.

A possible pathway through which leptin activates the histaminergic system was studied using in vivo microdialysis in rats. Intraperitoneal injection of leptin (1.3 mg/kg) caused a significant increase in hypothalamic histamine release, however, its intracerebroventricular injection (10 microg/rat) did not cause any significant changes in the release. Furthermore, leptin (1.3 mg/kg) had no effect on histamine release in rats whose chorda tympani nerves, a branch of the facial nerve which mediates taste information, were transected bilaterally. These findings indicate that leptin activates the histaminergic system by the peripheral signal inputs via the chorda tympani resulting in the suppression of food intake.

We have previously demonstrated the increase of histidine decarboxylase activity and histamine content in the murine hypothalamus after intracerebroventricular injection of lipopolysaccharide possibly due to inducible interleukin-1 beta (IL-1 beta). Therefore, we investigated the effects of IL-1 beta on brain histamine dynamics by directly injecting it into the tuberomammillary nucleus of the rat hypothalamus (TM) using an in vivo microdialysis method. Injection of artificial cerebrospinal fluid or recombinant murine IL-1 beta at 0.1 ng into the TM did not evoke a significant change in core temperature, however, a significant monophasic febrile response was observed following injection of IL-beta at more than 1 ng per animal. Histamine release in the anterior hypothalamic area in vivo was significantly augmented from 140 min to 360 min following injection of IL-1 beta at 10 ng dose. These results suggest the possibility that interrelationship between histamine and IL-1 beta may modulate the acute phase reaction in the central nervous system.

Exposure to bright light (2000 lx) for 2 h at the beginning of a 12 h light period (10 lx) resulted in about 1 h advances in the onset and termination of N-acetylserotonin (NAc5HT) synthesis in the pineal gland of NZBWF1 strain mice compared with those in mice not exposed to bright light. These effects are in contrast with the effect of exposure to bright light throughout the light period, which delayed the onset of pineal NAc5HT synthesis in NZB mice. The possible relationship of these effects with the mechanism of action of phototherapy of human affective disorder is discussed.

Histamine is reported to have different effects on shifting the circadian activity phase depending on its circadian administration time (CT). The delay-sensitive period is CT 12–15, and the advance-sensitive period is CT 0–3. The activity phase of rats was entrained by a new light-dark cycle within a week in groups treated with either saline or i.c.v. histamine at CT 12–15. However, on treatment at CT 0–3 the activity phase of the group treated with histamine was entrained by the new light-dark cycle in half the period required for entrainment in the control group.

Single neuronal activities were recorded extracellularly from slice preparations of the rat preoptic area and effects of histamine (0.01–10 μM) on the activities were examined with regard to thermosensitivities of the neurons. Superfusion of histamine increased the firing rate in 52 of 75 warm-sensitive neurons and in 22 of 41 thermally insensitive neurons in a dose-dependent manner. Ten (3%) warm-sensitive neurons and 6 (15%) thermally insensitive neurons were inhibited by histamine. Mepyramine (10 μM) (H 1 -antagonist), but not famotidine (H 2 -antagonist), blocked the histamine (10 μM) induced excitation in 19 (76%) of 25 warm-sensitive neurons and in 6 (75%) of 8 thermally insensitive neurons. These results suggest that histamine excites both warm-sensitive and thermally insensitive neurons in the preoptic area mainly via the H 1 -receptor.

Under urethane anesthesia, unit activity of locus coeruleus (LC) neurons was recorded extracellularly in pregnant and non-pregnant rats. The spontaneous firing of LC neurons was found to be reduced in pregnant rats. In addition, biochemical studies indicated that noradrenaline contents in the cerebral cortex, one of the major projection sites of LC neurons, were significantly higher in pregnant than non-pregnant rats. These results suggest that the electrical activity of noradrenergic neurons in the LC is reduced during gestation.