Invited Symposium: Neuronal Histamine Systems and Behavior


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Modifying Effects of Histamine on Circadian Rhythms and Neuronal Excitability

Contact Person: Leena Tuomisto (Leena.Tuomisto@uku.fi)

Histamine neurons, motility and feeding behaviour

Circadian rhythms in histaminergic activity

Histaminergic neurons in the posterior hypothalamus possess an intrinsic spontaneous activity (9,46,52) present during waking but depressed during sleep (64). The areas of distribution of histaminergic fibers include the suprachiasmatic nucleus (SCN), the main circadian pacemaker in mammals, and several other regions known to act either as secondary circadian pacemakers or to be linked to the SCN (1,34,40,51). Also the pineal gland and some components of the visual system have histaminergic innervation (29,36,41). Several functional and behavioural studies suggest that the histaminergic neurotransmitter system is a candidate to be a regulator of circadian and other rhythmic functions and of the sleep/wakefulness states (31,39,60).

Histaminergic activity of the brain can be estimated neurochemically either by directly measuring histamine release in vivo by push-pull cannula or microdialysis methods, or indirectly by measuring the histamine metabolites tele-methylhistamine (MHA) and tele-methylimidazole acetic acid (MIAA). In freely moving rats, a circadian rhythm in the release of histamine has been demonstrated from the anterior and posterior hypothalamus (30,43). The highest release was observed during the dark period when the rats were moving most actively. A clear circadian fluctuation of both MHA and MIAA exists in monkey cisternal CSF, the levels being higher during the daytime (45). Higher histaminergic activity during the awake period also in humans is suggested by the higher daytime levels of MHA in lumbar CSF of a group of children (17). There is also a short report on higher levels of histamine metabolites in the evening than in the morning in the CSF of healthy volunteers (56).

The correlation of histamine release to locomotion during constant darkness was even clearer than under changing lighting conditions. Therefore, it seems that histamine release itself is regulated by endogenous signals related to the circadian clock rather than the illumination changes (66). The fact that histamine is being released already before the lights are switched off (30,43), as well as the electrophysiologically recorded increase in the activity of the histaminergic neurons in anticipation of wakening and arousal (46,64), are in favour of this hypothesis. So far, no information is available about the stimulus, which transmits this kind of anticipatory signalling.

An example of the importance of histaminergic neurotransmission in maintaining the circadian release pattern of hormones is the circadian rhythm of corticosterone secretion. Inhibition of histamine synthesis with alpha-fluoromethylhistidine (FMH) causes a marked attenuation of the amplitude of corticosterone peaks and results in an almost arrhythmic state. This is mediated via control of ACTH secretion (12).

Motility and feeding behaviour

The activity of the histaminergic system affects several behavioural parameters including the overall ambulatory activity and food intake. The crucial role of H1 receptors in the maintenance of the circadian rhythm of locomotor activity has been confirmed in mice lacking H1 receptors. They have a shallow circadian rhythm, similar to that of animals treated with FMH, and show more ambulation during the light period (11,67,68), similar to that of animals treated with FMH, and show more ambulation during the light period. A similar shift from night to day occurs after FMH in feeding behaviour (5). On the other hand, if histamine concentrations and its availability in the synapses are increased by metoprine, which inhibits histamine metabolism, the circadian amplitude of food intake is not augmented and food intake is equally suppressed during day and night (20).

Serotonin is another biogenic amine closely related to circadian rhythmicity (35) and feeding behaviour (47). In the suprachiasmatic area, there is also an interaction between these two amines. Histamine release into the microdialysate is stimulated by 5-HT present in the perfusion fluid. The existence of a tonic stimulatory effect of endogenous 5-HT on histamine release is suggested by the enhancing effect on histamine release of dexfenfluramine, a 5-HT releaser and uptake blocker, and the inhibition caused by methysergide, a 5-HT2C/2A receptor blocker (19). An increased turnover rate of 5-HT in H1 receptor knockout mice suggests extensive interactions between histamine and 5-HT.

The periodicity of feeding is regulated not only by circadian cues but also by the subject's energy balance (53). Histaminergic neurotransmission has been implicated in the homeostatic maintenance of energy balance and in adaptive behaviour to environmental temperature (48,49,73); thus it may have dual functions in the regulation of food intake. A clear circadian rhythm in histamine release has been shown in fasted animals (66). Therefore, feeding behaviour may be only an additional factor influencing the apparent rhythmicity of histamine release (37).

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Phase shift of circadian activity

Several studies have indicated that H1 receptor agonists increase wakefulness and decrease slow wave sleep, whereas the antagonists have opposite effects (32,33). H3 receptors play an active part in these mechanisms by regulating histamine release (21). Histamine seems to induce phase shifts in the circadian rhythm much in the same way as light impulses. A single bolus of histamine, given i.c.v. at the beginning of the subjective dark period of rats postponed, during consecutive days, the start of the subjective dark period (14). These experiments were done in free running conditions in constant darkness, allowing the animals to follow their internal rhythm without entrainment by light or other external cues. Histamine in these conditions caused a complete phase delay of the monitored circadian activities, i.e. locomotion and drinking.

In similar conditions, hamsters were given a 15 min monochromatic light pulse 2 h after the start of the subjective dark period, to delay their acquired rhythm (6,15). The phase delay caused by this treatment was reduced by FMH. If the light pulse was given during the late dark hours, a phase advance was seen which was also reduced by FMH. These experiments suggest that histamine is able to mimic the influence of light in entraining the circadian rhythm, and that FMH is able to antagonize the physiological cue, i.e. light. This would imply a role for histaminergic neurons in mediating entrainment cues in the SCN.

The role of CNS histamine in modifying the behavioral rhythms is supported by in vitro studies showing direct effects of histamine on the SCN neurons. In the rat hypothalamic slice preparation, histamine modulates the firing of the SCN neurons. Depending on the experimental conditions, either inhibitory or excitatory effect dominates (22,50). Histamine induced a phase shift of the neuronal firing rate (4) when hamster SCN tissue was studied in vitro under conditions where the SCN neurons continue to fire spontaneously, rhythmically in phase with the previous light/dark cycle of the animal. This change in vitro was in line with the in vivo results (6). If histamine was applied early in the former dark period, the peak of firing appeared later, i.e. there was a phase delay. If it was applied during the late dark hours the neuronal firing started earlier, there was a phase advance.

Little is known about which histamine receptors are involved in the induction of those phase shifts. At the level of the main circadian oscillator, SCN, the direct excitatory effects of histamine on the neuronal firing seem to be mediated via H1 and the inhibitory effects via H2-receptors (22,50). In the slice preparation, the phase delaying effect of histamine appears to be via H1-receptors (4), but there is no information on which receptor type promotes the phase advance.

Based on in vivo studies, it has been proposed that the effects of histamine on the circadian rhythm are mediated through receptors other than histamine receptors. In the hamster, the light-induced phase shifts were reduced by FMH (6), but they could not be blocked by H1-, H2- or H3-antagonists (7). One of the possible receptors is the NMDA receptor, which is involved in the phase shifting effect of light in the hamster (3). Histamine has been shown to enhance NMDA receptor mediated responses in vitro, possibly through interaction with the polyamine binding site (2,65).

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Excitability of neurons, convulsive phenomena

There is clinical evidence that various drugs, e.g. brain penetrating antihistaminics and neuroleptics, which block histamine receptors may aggravate a pre-existing seizure disorder. When metoprine was given to rats, there was a clear dose-related protection from maximal electroshock seizures (59). Metoprine also reduced the severity of audiogenic seizures in genetically audiogenic seizure sensitive (AGS) rats (61) whereas the results with chemical seizures were controversary (54,55). These results suggested that histaminergic neurons are involved in mechanisms which inhibit generalizations of epileptic discharges in the brain perhaps as a part of an anticonvulsive inhibitory transmitter system.

In mice, elevation of brain histamine concentrations either by metoprine or L-histidine reduces the duration of electrically-induced clonic convulsions. Conversely, FMH, which decreases the brain histamine levels, increases the duration of clonic convulsions (73). The anticonvulsive effect seems to be mediated by H1-receptors; however, H3-receptors may also participate by regulating the release of endogenous histamine (69,71,72). Analogously, PET studies have revealed abnormal amounts of H1-receptors around the epileptic focus in human complex partial seizures (10).

Studies with mice have shown that the histaminergic system is important especially in young animals (70). This is in line with the clinical evidence that children are more sensitive to the proconvulsive side effects of drugs with H1-receptor antagonistic properties. This is supported also by the finding that CSF histamine concentration in a group of children with febrile convulsions was lower than in another group of febrile children without convulsions, suggesting a protective role for histamine against excessive neuronal excitation (16). Moreover, in AGS rats, lower endogenous levels of histamine were found in regions involved in seizure propagation (38,62).

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Effects of histamine on the arousal system

The ascending neurotransmitter systems, including cholinergic, noradrenergic and serotonergic, as well as the histaminergic neurons, have connections to the thalamus, an important gateway controlling and filtering impulses to the cerebral cortex. Histaminergic stimulation may switch the thalamic neurons from rhythmic burst-like firing to single-spike activity, a condition which favours accurate transmission and processing of sensory information, promoting wakefulness and arousal (26-28,57,58).

Little is known about the rhythms in histamine release or metabolism with respect to sleep stages. There is some evidence that during rebound sleep following a 72-hour REM sleep deprivation, rats have a decreased histamine turnover (MH/HA ratio) in the anterior hypothalamus. Due to the platform method used, however, stress may have interfered with those results (42). In anaesthetised animals, a negative correlation has been found between the ultradian rhythms of delta and theta EEG frequeNcy and the ultradian release of histamine (44). This suggests that a low release of histamine is accompanied with the EEG signs of sedation. It would be most interesting to see in behaving animals if the reverse is true with the signs of arousal.

The circadian amplitude of sleep-wakefulness cycle is flattened with FMH treatment, in the rat wakefulness is increased during the day and slow wave sleep is increased during the night (13,18). This would lead to sleep disturbances, and different disease states, accompanied by sleep disturbances, may also have changes in the brain histamine. For example patients with portal systemic encephalopathy (PSA) and many cirrhotic patients complain of sleep disturbances. These conditions can be simulated by the portacaval anastomosis (PCA) model in the rat. One of the most striking consequences of this operation is the remarkable elevation of brain histamine content soon after the operation (8) and the increased metabolism of histamine as a long term effect (23,24).

When cortical EEG was measured one and six months after the PCA operation, the signs of drowsiness, the synchronized low-frequency, high amplitude activities (delta waves and spindles), were reduced during the day-time recording period. There was a significant negative correlation between the spindling time and the frontal cortex histamine concentration (25). Thioperamide, an H3 blocker, reduced the incidence of thalamus-regulated EEG spindles. Furthermore, it reduced the spectral power of the low frequency (1,5-5 Hz) EEG (63). These results provide evidence for the involvement of endogenous brain histamine and H3 receptors in the regulation of the neocortical synchronization pattern, which is considered to be linked to arousal control.

In conclusion: 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 sleep-wakefulness cycles, food intake, motility and adrenocortical hormone release. In addition, a role for histaminergic neurons in 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 FMH 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 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.

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Tuomisto, L.; (1998). Modifying Effects of Histamine on Circadian Rhythms and Neuronal Excitability. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/huston/tuomisto0834/index.html
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