Modifying effects of histamine on circadian rhythms and neuronal excitability.

Histaminergic activity shows a clear circadian rhythm: high levels during the active period (in rodents at night, in monkeys and humans during the day), and low levels during the sleep period. Histamine appears to be necessary for the maintenance of the circadian rhythmicity of the adrenocortical hormone release, locomotor activity and food intake, and the sleep-wakefulness cycle. In addition, a role for histaminergic neurons in the light entrainment is implicated. In phase shift studies, histamine given centrally seems to entrain the activity rhythm in the same way as light impulses and inhibition of histamine synthesis seems to block the entrainment by light. Importantly, histamine participates in the control of arousal and may be implicated in the sleep disturbances in hepatic encephalopathy. Furthermore, evidence suggests a role for histamine in overall neuronal excitability and seizure susceptibility both in animals and humans. Thus, we conclude that histamine may exert modifying effects on circadian rhythmicity and neuronal excitability.

Increased density of brain histamine H(1) receptors in rats with portacaval anastomosis and in cirrhotic patients with chronic hepatic encephalopathy.

The binding properties and the regional densities of histamine H(1) receptors were studied in brain of rats with portacaval anastomosis (PCA) and in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy (HE). Receptor binding studies and quantitative receptor autoradiography were performed, employing [(3)H]mepyramine. Histamine H(1) receptors in rat brain displayed a higher density and a lower affinity compared with control human frontal cortex. Specific [(3)H]mepyramine binding was heterogeneously distributed throughout the brain in both species. In human brain, binding was highest in the parietal and temporal cortices and lowest in caudate-putamen. In rat brain, binding was highest in the suprachiasmatic nucleus, dentate gyrus of the hippocampus, ventromedial hypothalamus, and nucleus accumbens. Cortical tissue from PCA rats and frontal cortical tissue from HE patients contained significantly increased densities (B(max)) of H(1) receptors. A selective increase in H(1) receptor density was also observed in parietal and insular cortices of HE patients. Results of the present study suggest a selective up-regulation of brain H(1) receptors in PCA rats and in patients with HE. The central histaminergic system is implicated in the control of arousal and circadian rhythmicity. Previous studies have shown that blockade of H(1) receptors in PCA rats results in improved locomotor activity and circadian rhythmicity scores. The present findings suggest that cortical histaminergic hyperactivity could contribute to the neuropsychiatric symptoms characteristic of human HE, and that selective histamine H(1) receptor antagonists could be beneficial in the prevention and treatment of some of the symptoms of HE in cirrhotic patients.

Effects of the histamine H(1) receptor blocker, pyrilamine, on spontaneous locomotor activity of rats with long-term portacaval anastomosis.

To find out whether the changes in the brain histaminergic system are involved in the pathophysiology of portal-systemic encephalopathy, we examined the effects of histamine H(1) receptor blockade on spontaneous locomotor activity, feeding, and circadian rhythmicity in rats with portacaval anastomosis (PCA). Pyrilamine, an H(1) receptor blocker (15 mg/kg/day), was delivered with osmotic minipumps. Spontaneous locomotor activity was recorded for 72 hours in the open-field with an electromagnetic detector. Food intake was monitored twice daily at the end of the light (7 PM) and the dark (7 AM) phases for 3 days. Histamine H(1) receptor density in the suprachiasmatic nucleus (SCN) was examined with receptor autoradiography, employing [(3)H]pyrilamine. PCA surgery led to decreased movement time and velocity and flattened amplitude of the circadian rhythms of locomotion and feeding. In sham-operated rats, pyrilamine significantly decreased the movement time and velocity, as well as the total food consumption and completely abolished the circadian rhythmicity of locomotion. In contrast, pyrilamine increased the movement time and velocity in PCA-operated rats, particularly in the dark phase, and improved the precision of the circadian rhythms of locomotion and feeding. Histamine H(1) receptor density was not altered by PCA surgery, whereas pyrilamine treatment led to the complete blockade of H(1) receptors in both sham- and PCA-operated rats. We suggest that histaminergic imbalance has contributed to the generation and maintenance of the decreased spontaneous locomotor activity and altered circadian rhythmicity following PCA surgery in the rat, probably via an H(1) receptor-mediated mechanism.

Hypothalamic histamine, growth rate, plasma prolactin and growth hormone levels in rats with long-term portacaval anastomosis.

OBJECTIVE AND DESIGN: Histamine can modulate feeding behaviour and hormone release; therefore we examined the hypothalamic histamine system, the growth pattern and the serum levels of prolactin and growth hormone in rats with portacaval anastomosis (PCA). MATERIAL: The growth rate of 30 PCA- and 30 sham-operated male Han:Wistar rats was monitored for 6 months. Thirteen sham and 9 PCA rats were used for biochemical studies. METHODS: Histamine was assayed by HPLC, tele-methylhistamine by GC-MS, prolactin and growth hormone by RIA. Student's t-test was used to compare the groups. RESULTS: Six months after surgery, the PCA rats exhibited marked growth retardation (weight gain of 20 g vs. 140 g for the sham rats; p < 0.001), increased plasma levels of prolactin (9.7 +/- 2.4 vs. 3.6 +/- 0.6; p<0.01) and unaltered growth hormone levels (6.2 +/- 0.5 vs. 8.1 +/- 1.0). A six-fold elevation of histamine concentration (29.5 +/- 3.9 vs. 4.8 +/- 0.4; p<0.001) and a two-fold increase of tele-methylhistamine levels (1.8 +/- 0.1 vs. 0.8 +/- 0.02; p<0.001) were found in hypothalamus. CONCLUSION: We suggest that increased histaminergic activity in the hypothalamus may be involved in the development of growth retardation and in the enhanced basal secretion of prolactin in male rats with long-term PCA.

Brain histamine levels and neocortical slow-wave activity in rats with portacaval anastomosis.

To determine whether the increased histamine levels in the brain of rats with portacaval anastomosis (PCA) are associated with the development of sleep disturbances during the light phase, the neocortical slow-wave activity of PCA-operated rats was examined with electroencephalography (EEG) 1 month and 6 months after the surgery. The tissue levels of histamine, tele-methylhistamine, 5-hydroxytryptamine (5-HT) (serotonin), and 5-hydroxyindole-3-acetic acid (5-HIAA) in frontal cortex were assayed by high-performance liquid chromatography 6 months after the surgery. PCA surgery led to changes in the synchronized, low-frequency, high-amplitude frontal cortex EEG activity recorded during the light phase. Delta-wave amplitude but not delta time was significantly decreased, whereas both spindle amplitude and spindling time were significantly decreased. There were also significant age-related changes, presented as increases in the duration of spindles and the amplitude of both delta waves and spindles. PCA-operated rats showed a change in the pattern of EEG activity with increasing age similar to sham-operated rats. This suggests that once established, the resetting of the systems regulating the sleep-waking behavior is being maintained with time. The tissue levels of both histamine and metabolite in the frontal cortex were increased, whereas the serotonin system showed only an increase in the level of the metabolite. There was a significant negative correlation between the spindling time and the tissue histamine levels. We suggest that histamine, which participates in the control of vigilance, sleep, and wakefulness, as well as in the modulation of circadian rhythmicity, may play a role in the development of sleep disturbances in rats with PCA.

Brain histamine H3 receptors in rats with portacaval anastomosis: in vitro and in vivo studies.

The long-term effects of portacaval anastomosis (PCA) on histamine H3 receptors in rat brain were studied by in vitro and in vivo methods. The overflow of histamine from the anterior hypothalamus and from cortex after long-term PCA was determined by in vivo microdialysis. The binding properties of [3H]-R-alpha-methylhistamine in membranes from cortex, cerebellum, and rest of brain (ROB) were examined with saturation binding experiments. The regional distribution of [3H]-R-alpha-methylhistamine binding sites in the brain of sham- and PCA-operated rats was assessed also with autoradiography. The tissue levels of histamine were significantly elevated in cortex and ROB of PCA-operated rats. In addition, the spontaneous and K+-evoked overflow of histamine from anterior hypothalamus, and the thioperamide-induced overflow from both anterior hypothalamus and cortex were increased after chronic PCA. In spite of the significantly elevated tissue concentrations and the moderate increase in histamine release, the binding properties of [3HI-R-alpha-methylhistamine to cortical membranes were not significantly changed. However, the autoradiography study did reveal a decrease in [3H]-R-alpha-methylhistamine binding density, particularly in striatum and cortex, where H3 receptors are located mainly at non-histaminergic neurons. In conclusion, we suggest that there is a region-selective increase in the histaminergic activity in chronic PCA, which leads to the down-regulation of somadendritic and pre-synaptic H3 receptors located at non-histaminergic neurons. At the same time, the autoreceptor mediated control of histamine neuronal activity via pre-synaptic H3 receptors located at histaminergic neurons is preserved after long-term PCA.

Long-term effects of portacaval anastomosis on the 5-hydroxytryptamine, histamine, and catecholamine neurotransmitter systems in rat brain.

Portacaval anastomosis (PCA) in the rat is used as a model for portal systemic encephalopathy. Changes in the serotonergic, histaminergic, and catecholaminergic neurotransmitter systems are often found shortly after PCA. We have examined the long-term effects of PCA on the aminergic systems in brains of male Wistar rats, which 8 months previously had been subjected to PCA. Precursors, amines, and metabolites were assayed by HPLC. Eight months after PCA, the catecholamine levels were unchanged in all brain regions. In contrast, tryptophan was evenly increased throughout the brain. The accumulation of 5-hydroxytryptophan after decarboxylase inhibition (NSD-1015; 100 mg/kg i.p.) and the endogenous levels of 5-hydroxyindoleacetic acid were significantly higher in PCA rats, particularly in the hypothalamus and midbrain, whereas 5-hydroxytryptamine concentrations were unchanged. Histamine levels were elevated throughout the brain with the greatest increase found in the hypothalamus and in the striatum. tele-Methylhistamine levels were significantly elevated in cortex and hypothalamus. We conclude that 8 months after PCA, catecholaminergic systems had reestablished their homeostasis, whereas serotonergic and histaminergic systems still show profound disturbances in their function. With histamine, this is reflected as an increase in the amounts of both transmitter and metabolite; serotonergic neurons respond by increasing only the level of the metabolite.

Gastric histamine content and ulcer formation in rats with ethanol-induced injury. Effects of cinnarizine and flunarizine.

The effects of the calcium antagonists cinnarizine and flunarizine on gastric histamine content and ulcer formation in rats with ethanol-induced injury were studied. Gastric ulcers were inflicted by oral application of 50% or 100% ethanol solution. Cinnarizine (20 mg/kg), flunarizine (10 mg/kg) and cimetidine (100 mg/kg) were administered orally 1 h before ethanol. Histamine was assayed fluorometrically. No effect of the tested drugs on 50% ethanol-induced gastric damage was observed. Cinnarizine and flunarizine inhibited 100% ethanol-induced lesion formation by 71% (p < 0.01) and 20% (p > 0.05), respectively. The inhibition exerted by cimetidine was 54% (p < 0.05). Gastric histamine content was not affected by 50% ethanol, while 100% ethanol decreased it two-fold. None of the tested drugs induced significant changes in gastric histamine levels. No correlation was obtained between the ulceroprotective effect of the used calcium antagonists and the gastric histamine content in ethanol-induced injury.

[The effect of the calcium channel blockers cinnarizine and flunarizine on the duration of hexobarbital-induced sleep i rats]. / Vliianie blokatorov kal'tsievykh kanalov tsinnarizina i flunarizina na prodolzhitel'nost' geksobarbitalovogo sna u krys.

The effect of the calcium channel blockers cinnarizine (20 mg/kg) and flunarizine (10 mg/kg) on hexobarbital sleeping time in rats has been studied. We have found that cinnarizine when applied intraperitoneally once 1 h or 4 h before hexobarbital and repeatedly for 5 days once daily prolongs sleeping time significantly. When cinnarizine has been introduced simultaneously with phenobarbital (60 mg/kg) for 5 days once daily the sleeping time that was expected to be shortened by phenobarbital only has been obtained to return to control values. Flunarizine has not been found to affect sleeping time significantly either alone or in the presence of phenobarbital. Latencies have not been altered by any of both agents.