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.
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.
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. (HEPATOLOGY 1999;29:340-346.)Portal-systemic encephalopathy (PSE) is a potential longterm complication in any patient with chronic liver disease receiving a portacaval shunt. The biochemical changes that occur in the plasma and brain of patients with PSE can be reproduced in the rat with portacaval anastomosis (PCA). 1 The clinical presentation of PSE at early stages is dominated by the diminished total duration of slow-wave sleep, the disorganization of the normal nocturnal sleep cycles, the reversed sleep patterns, and the decrease in the spontaneous voluntary movement. Moreover, according to a recent study, approximately half of the cirrhotic patients without overt encephalopathy complain of sleep disturbances. 2 The neurological changes that are consequences of a portacaval shunt in the rat are also manifested as disruptions of sleep patterns and diurnal rhythms, changes in the vigilance or motor activity, and neuromuscular coordination. [3][4][5][6][7][8][9][10] Although much research has been performed to reveal the pathogenesis of PSE, the exact mechanisms responsible for the generation and maintenance of the sleep disturbances are still unclear. Until now, they have been attributed mainly to modification of serotonergic neurotransmission. 9,11 One of the most striking co...
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