Atsushi Yamatodani

Circadian rhythm of histamine release from the hypothalamus of freely moving rats

Using an in vivo microdialysis technique coupled with HPLC-fluorometry, the release of neuronal histamine from the anterior hypothalamic area was monitored continuously in conscious, freely moving rats under a 12:12 h light:dark cycle. Spontaneous locomotor activity of the rats was measured simultaneously using a locomotor activity counter. Histamine release gradually increased in the second half of the light period (1400-2000) and the average histamine release during the dark period (2000-0800, 0.20 +/- 0.02 pmol/30 min) was significantly higher than that during the light period (0.12 +/- 0.01 pmol/30 min). This clear circadian change in the release suggests that the central histaminergic system is related to the circadian rhythm of rats.

In vivo release of neuronal histamine in the hypothalamus of rats measured by microdialysis

SummaryUsing an in vivo intracerebral microdialysis method coupled with an HPLC-fluorometric method, we investigated the extracellular level of endogenous histamine in the anterior hypothalamic area of urethaneanaesthetized rats. The basal rate of release of endogenous histamine in the anterior hypothalamic area measured by this method was 0.09 + 0.01 pmol/20 min. When the anterior hypothalamic area was depolarized by infusion of 100 mM K+ through the dialysis membrane or electrical stimulation at 200 μ A was applied through an electrode implanted into the ipsilateral tuberomammillary nucleus, histamine release increased to 175% and 188%, respectively, of the basal level. These increases were completely suppressed by removal of extracellular Ca2+. The basal release of histamine was also suppressed after infusion of 10−6 M tetrodotoxin or i.p. administration of 100 mg/kg of α-fluoromethylhistidine. On the other hand, 3-fold increase in the basal release was observed after i. p. administration of 5 mg/kg thioperamide. These results clearly indicate that both the basal and evoked release of histamine measured by our method are of neuronal origin.

Glutamatergic regulation of histamine release from rat hypothalamus.

A microdialysis method was used to study the effects of glutamate on the in vivo release of histamine from the anterior hypothalamic area of rats anesthetized with urethane. Infusion of 1 mM glutamate through a microdialysis probe increased histamine release to about 150% of the basal release. Infusion of N-methyl-D-aspartate (NMDA, 0.1 mM) caused a similar increase. Glutamate-evoked histamine release was completely blocked by D-(-)-2-amino-5-phosphonopentanoic acid (AP5, 0.1 mM), a specific antagonist of NMDA receptors. AP5 alone also reduced histamine release to about 60% of the basal level. Infusion of tetrodotoxin (100 nM) reduced histamine release to about 30% of the basal release, but had no effect on glutamate-evoked release. These results clearly indicate that glutamate enhances histamine release through NMDA receptors located on histaminergic nerve terminals, and suggest that there is a tonic glutamatergic regulation of this release.

Structure and Functions of the Histaminergic Neurone System

Since the first issue on histamine in the Handbook of Pharmacology (Rocha E Silva 1966), in which only eight pages were devoted to brain histamine (White 1966), great progress has been made in this field. Pioneering neurochemical studies by Schwartz and his colleagues (see Scheartz et al. 1986a) were corroborated and refined in detail by immunohistochemical demonstration of the histaminergic neurone system in rat brain (Watanabe et al. 1984; Panula et al. 1984; Steinbusch and Mulder 1984). Now there is convincing evidence that histamine is a neurotransmitter or a neuromodulator in the mammalian brain.

EFFECT OF HISTAMINE DEPLETION ON THE CIRCADIAN AMPLITUDE OF THE SLEEP-WAKEFULNESS CYCLE

Behavioral states of rats were automatically classified with a newly developed computer program into three sleep stages (awake, slow-wave sleep and REM sleep) from continuous long-term EEG and EMG recordings for several circadian cycles under entrained circumstances (L:D = 12:12). Histamine was depleted by 100 mg/kg intraperitoneal administration of a specific inhibitor of its synthesis, alpha-fluoromethylhistidine, in the mid-light period. This treatment had no effect on the amount of each sleep stage in the total 24-h period or in the light period, but caused significant increases in slow-wave sleep and REM sleep in the dark period. Equivalent decrease in the awake stage during the dark period was also observed. As a result, histamine depletion decreased the light:dark ratio of slow-wave sleep. These findings suggest that decrease of the histamine content of the brain attenuated the circadian amplitude of sleep-wakefulness by suppressing the surge of wakefulness during the dark period. From these results, histamine is suggested to modulate the circadian amplitude of the sleep-wakefulness cycle.

Effect of Histamine Depletion on Circadian Variations of Corticotropin and Corticosterone in Rats

The effects of cerebral histamine depletion induced by alpha-fluoromethylhistidine (FMH) on corticotropin (ACTH) and corticosterone secretions were examined. Neither acute nor chronic FMH treatment altered the corticoadrenal responses to three types of stress: transposition, immobilization and water immersion. And exposure to stress did not affect the hypothalamic content of histamine. However, chronic intracerebral treatment with FMH had a significant effect on the circadian rhythm of the plasma corticosterone (CS) level in rats. Namely, it caused a marked attenuation of the amplitude of the peaks of the CS level resulting in an almost arrhythmic state. The maximum differences between FMH treated and untreated groups were seen at 8.00 and 20.00 h, the times when the illumination condition changed (light onset 8.00 h). This treatment with FMH also had a similar effect on the plasma ACTH concentration; namely the plasma ACTH level in the saline treated group was lower than that of the FMH-treated group at light onset and higher than the latter at dark onset, but was similar to the latter at other sampling points. These results indicate the histaminergic modulation of the circadian rhythm of hormonal secretion of the adrenal cortex and show that this phenomenon is mediated through the central nervous system by an influence on the rhythm of hypophyseal ACTH secretion possibly through alteration in the concentration of corticotropin-releasing factor.

Regional distribution of histamine in the brain of non-mammalian vertebrates.

The histamine contents in the brains of various species of non-mammalian vertebrates were determined by an HPLC-fluorometric method. The whole brain contents of histamine in birds (200-500 pmoles/g) were comparable to those in mammals, but were higher in reptiles (1000-13500 pmoles/g) and amphibia (1600-2200 pmoles/g) and lower in teleosts (10-50 pmoles/g). In all species, histamine was unevenly distributed, being present at highest concentrations in the diencephalon, except in teleosts, in which its content was highest in the telencephalon. The brain histamine contents were proportional to the reported densities of histamine-immunoreactive fibers.