Brain Histamine Levels and Neocortical Slow–Wave Activity in Rats With Portacaval Anastomosis

Abstract

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...

Increased Density of Brain Histamine H1 Receptors in Rats With Portacaval Anastomosis and in Cirrhotic Patients With Chronic Hepatic Encephalopathy

“…[6][7][8] Relating the functions controlled by histamine to the clinical presentation of HE, it appears a priori that histamine could participate in the pathogenesis of the sleep disturbances, decreased spontaneous voluntary movement, and increased plasma prolactin levels in patients with HE and in the hormonal changes, growth retardation, and the altered vigilance, locomotor activity, and circadian rhythmicity in rats with PCA. Consistent with these possibilities, we have previously shown that blockade of central histamine H 1 receptors with the specific antagonist, pyrilamine (mepyramine), restores the altered circadian rhythmicity of feeding and locomotor activity.…”

“…Among the least exploited consequences of HE are the marked changes in the brain histaminergic system, which have been previously documented both in patients with HE 3 and in rats with portacaval anastomosis (PCA), a well-established animal model of the disease. [4][5][6][7][8] There is substantial evidence that histamine acts as a neurotransmitter in mammalian brain. 9 Histaminergic neurons are located exclusively in the tuberomammillary nucleus of the posterior hypothalamus and send their varicose fibers to almost every region of the brain.…”

Effects of the histamine H1 receptor blocker, pyrilamine, on spontaneous locomotor activity of rats with long-term portacaval anastomosis

“…PSE has been described as a disorder of multiple neurotransmitter systems. 13 Specifically, the histaminergic synaptic imbalance, which becomes apparent shortly 14,15 and persists for at least 8 months after surgery, 12,[16][17][18] is among the most interesting consequences of portacaval shunting in the rat.…”

“…12,17,18 These rats have excessively high tissue levels of histamine in brain regions particularly enriched in histaminergic neurons and/or cell bodies. 12,17 Furthermore, the spontaneous, as well as the depolarizationinduced and pharmacologically induced histamine release from anterior hypothalamus are significantly increased in these rats.…”

“…We have previously suggested that histaminergic synaptic imbalance may have contributed to the sleep disturbances in rats with PCA. 18 We have now examined the effects of histamine H 1 receptor blockade on feeding, locomotor activity, and circadian rhythmicity in rats with long-term PCA to find out whether the modified histaminergic neurotransmission in the brain of rats with portacaval anastomosis 6 months after surgery 12,[16][17][18] has also participated in the generation and maintenance of the disturbances in the circadian rhythmicity of feeding and locomotor activity. Pyrilamine (mepyramine), a selective and high-affinity H 1 receptor antagonist, 29 was used to block histamine H 1 receptors in the CNS.…”