Takehiko Watanabe

Distribution of the histaminergic neuron system in the central nervous system of rats; a fluorescent immunohistochemical analysis with histidine decar☐ylase as a marker

The distribution of histidine decarboxylase-like immunoreactivity (HDCI) in the rat central nervous system was studied by the indirect immunofluorescence technique. HDCI cell bodies were concentrated in the posterior hypothalamic area, such as in the tuberal magnocellular nucleus, caudal magnocellular nucleus, posterior hypothalamic nucleus and lateral hypothalamus just lateral to the fasciculus mammillothalamicus at the level of the posterior hypothalamic nucleus. Extensive networks of HDCI fibers of various densities were found in many areas of the brain; they were particularly dense in the hypothalamus but were also found in the following areas: rostrally in the cerebral cortex, olfactory nuclei, medial amygdaloid nucleus, n. tractus diagonalis, and bed nucleus of the stria terminalis, and caudally in the central gray matter of the midbrain and pons, auditory system, n. vestibularis medialis, n. originis nervi facialis, n. parabrachialis, n. commissuralis, n. tractus solitarii, and n. raphe dorsalis.

Evidence for the presence of a histaminergic neuron system in the rat brain: An immunohistochemical analysis

Histamine-containing cells in rats were identified by indirect immunofluorescent histochemistry using an antibody raised against histidine decarboxylase (HDC), the enzyme forming histamine, which was purified from fetal rat liver. HDC-like immunoreactive (HDCI) structures could be detected in the brain as well as in peritoneal mast cells and basal-granulated cells in deep crypts of the gastric mucosa of rats. Numerous HDCI neurons were found in the posterior hypothalamic area and HDCI nerve fibers with a varicose appearance of fluorescence were widely distributed in various regions of the brain.

Histaminergic axons in the neostriatum and cerebral cortex of the rat: a correlated light and electron microscopic immunocytochemical study using histidine decar☐ylase as a marker

Histaminergic nerve fibers and their axonal varicosities in the neostriatum and cerebral cortex were light and electronmicroscopically examined by means of peroxidase-antiperoxidase immunocytochemistry with histidine decarboxylase (HDC) as a marker. A majority of HDC-like immunoreactive axonal varicosities observed in serial thin sections for electron microscopy exhibited no synaptic contacts in either the neostriatum or cerebral cortex. The remaining small proportion of immunoreactive axonal varicosities formed synaptic contacts with non-immunoreactive dendritic shafts and spines.

Effect of α-fluoromethylhistidine, a suicide inhibitor of histidine decarboxylase, on histamine levels in mouse tissues

Abstract The effects of α-fluoromethylhistidine (α-FMH), a new suicide inhibitor [Kollonitsch et al., Nature, Lond. 274 , 906 (1978)], on histidine decarboxylase (HDC) activities and histamine contents of the skin, fundic stomach and brain of mice were investigated. Four hours after i.p. administration of α-FMH to ddy mice, HDC activities in the brain, stomach and skin had decreased in a dose-dependent way (1–25 mg/kg), by a maximum of 90–95%. The histamine levels in the brain and stomach decreased to 50% of the control levels, whereas the level in the skin did not change at all. The time courses of changes in HDC activities and histamine levels were examined. After i.p. administration of 25 mg/kg of α-FMH, HDC activities in these tissues dropped rapidly within 1 hr. Recovery of HDC activities in the stomach and skin began within 12 hr, but the activity in the brain remained low for 24 hr, confirming the result of Garbarg et al. [ J. Neurochem. 35 , 1045 (1980)]. The histamine content of the stomach decreased to 40% of the original level in 8 hr and recovered within 12 hr, whereas that in the brain decreased to 50% and remained low for more than 24 hr. The histamine content of the skin did not change. These results suggest that the histamine level that was not reduced by α-FMH was derived from mast cells. During the above experiments, no behavioral changes of the animals were detected. α-FMH prevented the increase in HDC activity in mouse kidney on day 18 of gestation when administered i.p. every 12 hr from day 13. No abnormalities were seen in fetuses and neonates after this treatment. It is concluded that α-FMH causes depletion of newly synthesized histamine in situ and, thus, is useful for studies on histamine.

Origins of histamine-containing fibers in the cerebral cortex of rats studied by immunohistochemistry with histidine decar☐ylase as a marker and transection

The origins of histamine-containing fibers in the cerebral cortex were examined by means of the retrograde tracer technique of horseradish peroxidase (HRP)-immunohistochemistry with histidine decarboxylase (HDC) as a marker for the histamine neuron system. Total transection of the brain rostral to the posterior hypothalamus resulted in disappearance of HDC-like immunoreactive (HDCI) fibers in the cerebral cortex, but total transection caudal to the posterior hypothalamus did not decrease the number of HDCI fibers in the cortex, suggesting that HDCI fibers in the cerebral cortex originate in the posterior hypothalamus. The projection of HDCI neurons from the posterior hypothalamus to the cerebral cortex seemed to be bilateral because hemi-transection of the brain rostral to the posterior hypothalamus resulted in a bilateral decrease of HDCI fibers in the cerebral cortex with ipsilateral predominance. After injection of HRP into the cerebral cortex, numerous cells containing both HRP granules and HDCI structures were found bilaterally in the tuberal, caudal and postmamillary magnocellular nuclei, with ipsilateral predominance. These findings indicate that HDCI cells in the above nuclei give rise to axons extending bilaterally to the cerebral cortex.

Effects of α-fluoromethylhistidine on sleep-waking parameters in rats

Effects of alpha-fluoromethylhistidine (FMH), an irreversible inhibitor of histidine decarboxylase, on the sleep-waking parameters were studied in rats for 24 hours. Intraperitoneal administration of FMH (100 mg/kg) at 11:30 hr resulted in a longer sleep latency compared with the control values. Hour-to-hour analyses revealed that wakefulness (W) time decreased (from 20:00 to 07:00 hr) and slow wave sleep (SS) time increased (from 19:00 to 06:00 hr) in the night. Paradoxical sleep (PS) time did not parallel the SS changes; it was increased significantly from 07:00 to 11:00 hr in the next morning. The influence of FMH seemed to be divided into direct, immediate action (increase of W) and late, prolonged action (decrease of W), and the results obtained support the histamine arousal hypothesis.

Increase in histidine decarboxylase activity in mouse skin after application of the tumor promoter tetradecanoylphorbol acetate

Summary A tumor promoter in two-step carcinogenesis, 12-O-tetradecanoylphorbol-13-acetate, was painted on the dorsal skin of C57BL/6 mice. Within 12 hr after a single application of TPA the activity of histidine decarboxylase increased 10 times. The activity of ornithine decarboxylase also increased, but its increase was significantly earlier than that of histidine decarboxylase. Preincubation of a crude extract of the skin with α-fluoromethyl-histidine, a suicide inhibitor of histidine decarboxylase, completely inhibited the increase in histidine decarboxylase activity, indicating the distinct natures of the two decarboxylases.

Effect of α‐Fluoromethylhistidine on the Histamine Content of the Brain of W/Wv Mice Devoid of Mast Cells: Turnover of Brain Histamine

Abstract: In the brains of W/Wv mutant mice that have no mast cells, the histidine decarboxylase (HDC) level is as high as in the brain of congenic normal mice (+/+), but the histamine content is 53% of that of +/+ mice. The effects of a‐fluoromethylhistidine (α‐FMH) on the HDC activity and histamine content of the brain of W/Wr and +/+ mice were examined. In both strains, 30 min after i.p. injection of α‐FMH the HDC activity of the brain had decreased to 10% of that in untreated mice. The histamine content decreased more gradually, and after 6 h about half of the control level remained in +/+ mice, whereas histamine had disappeared almost completely in W/Wv mice. It is concluded that the portion of the histamine content that was depleted by HDC inhibitor in a short time is derived from non‐mast cells, probably neural cells. The half‐life of histamine in the brain of W/Wv mice was estimated from the time‐dependent decrease in the histamine content of the brain after administration of a‐FMH: 48 min in the forebrain, 103 min in the midbrain, and 66 min in the hindbrain.

Histaminergic projections from the premammillary and posterior hypothalamic region to the caudate-putamen complex in the rat

Immunofluorescence, using antibodies to histamine and to histidine decarboxylase, was combined with retrograde axonal tracing by injecting Granular Blue into the caudate-putamen complex. Evidence is presented for the existence of histaminergic as well as non-histaminergic projections from the posterior hypothalamus and the premammillary region to the caudate-putamen complex. The majority of the histaminergic neurons projecting to this brain region are localized in the nuclei caudalis magnocellularis and caudalis magnocellularis postmammillaris. Roughly 20-25% of the histaminergic neurons in these cell groups innervate the caudate-putamen complex.

Changes in the feeding behavior of rats elicited by histamine infusion

In this study, we examined the effect of a putative neurotransmitter or a neuromodulator histamine (HA) on the feeding behavior to elucidate its physiological function in the central nervous system. Rats were implanted with a cannula into the suprachiasmatic nucleus through which HA was continuously infused for 200 hours with an Alzet osmotic minipump. The food intake was recorded automatically. This infusion resulted in decrease in food intake during the dark period and increase in it during the light period which contributed to the decrease in total food intake and increase in the percentage of food intake during the light period. Percentage of food intake during the light period is a good index of the amplitude of the circadian rhythm. Presumably, HA is concerned not only in the meal size, but also in the chronological aspect of the feeding behavior. The administration of H1-antagonist, pyrilamine, antagonized the HA induced increase in food intake during the light period. These findings suggest that continuous infusion of HA affected the feeding behavior which is possibly mediated through the H1-receptors in rat brain.