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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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Histamine Actions in the Central Nervous System


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Histamine in the brain may act as both a neuromodulator and classical transmitter

Histaminergic neurons appear to provide a variety of signaling mechanisms in the brain. A “neuromodulator” role for histamine has received the most attention. Thus, activation of a small number of tuberomammillary cells is thought to release histamine, which subsequently increases excitability in target cells distributed widely throughout the brain [7]. As mentioned, most of this histamine release is nonsynaptic, implying wide diffusion of the modulator. Such a system is consistent with the characteristics of known histamine receptors, which function through “slow” transmission mechanisms (see Chap. 10) requiring the production of intracellular second messengers (Table 14-2). However, it is becoming clear that neuronal histamine is also capable of providing discrete, fast neurotransmission in the brain. For example, electrical stimulation of the tuberomammillary cells has been shown to evoke fast excitatory postsynaptic potentials in phasically firing supraoptic neurons, effects that are mimicked by application of histamine and blocked by histamine antagonists [30]. These findings imply that, like serotonin (see Chap. 13), histamine may be able to activate both ligand-operated channels and receptors linked to second messengers. The former remain to be identified, however.

Histaminergic neurons can regulate and be regulated by other neurotransmitter systems

A number of other transmitter systems can interact with histaminergic neurons (Table 14-1). As mentioned, the H3 receptor is thought to function as an inhibitory heteroreceptor. Thus, activation of brain H3 receptors decreases the release of acetylcholine, dopamine, norepinephrine, serotonin and certain peptides. However, histamine may also increase the activity of some of these systems through H1 and/or H2 receptors. Activation of NMDA, μ opioid, dopamine D2 and some serotonin receptors can increase the release of neuronal histamine, whereas other transmitter receptors seem to decrease release. Different patterns of interactions may also be found in discrete brain regions.

Histamine in the central nervous system may participate in a variety of brain functions

Several of the suspected physiological roles for histamine are related to its ability to increase the excitability of CNS neurons. In fact, in the brain, histamine has been suggested to be a regulator of “whole brain” activity [7]. For example, mutant mice lacking the H1 receptor show defective locomotor and exploratory behaviors [30a]. Closely related may be the role of histamine as a mediator of arousal. All available evidence from several species shows that histaminergic neurons, when activated, increase wakefulness and induce electrographic arousal. The H1 receptor in the ventrolateral hypothalamus is one important site for this effect [31], but actions on the thalamus and cerebral cortex may also be significant. The onset of sleep has been traced to cells in the ventral preoptic area of the hypothalamus, which, when activated, are thought to turn off the histaminergic tuberomammillary cells. Thus, histamine is an important regulator of sleep—wake cycles and probably contributes to the diurnal changes in other brain functions as well.

Histamine also reduces seizure activity, another H1 receptor-mediated effect. H1 antagonists increase seizure onset and/or seizure duration in humans and animals. H1 receptor numbers are increased in some types of human epileptic foci [12]. Pharmacological studies suggest that centrally administered histamine can also enhance learning and retention of tasks in laboratory animals. However, the role of histaminergic neurons in these tasks is complex, and contradictory findings have been reported [31a].

Histamine is a powerful regulator of many hypothalamic functions. Neuroendocrine responses, especially vasopressin release, are physiologically regulated by histaminergic neurons [30,32]. Hypothalamic histamine may also participate in the physiological regulation of oxytocin, prolactin, adrenocorticotrophic hormone (ACTH) and β-endorphin release. Regulation of the latter two occurs by changes in release of both corticotropin-releasing hormone and vasopressin [33,34]. Both H1 and H2 receptors seem to function in the histaminergic control of pituitary function.

Neuronal histamine is also an effective modulator of both food and water intake [12,34a]. Histamine and compounds that increase extracellular histamine concentrations are powerful suppressants of food intake. An action on the H1 receptor in the ventromedial hypothalamus (VMH) seems to account for these effects [35]. Evidence that histamine contributes to the physiological control of appetite includes findings with genetically obese Zucker rats, which have very low concentrations of hypothalamic histamine. Histamine is also a powerful dipsogen (an agent that induces drinking), whether administered systemically or directly into the hypothalamus. Multiple hormonal and neuronal mechanisms may contribute to these effects [36]. Other suggested roles for histamine in the regulation of vegetative functions include thermoregulation [37], regulation of glucose and lipid metabolism [38] and control of blood pressure.

Histamine also induces antinociceptive, that is, pain-relieving, responses in animals after microinjection into several brain regions [39]. Both neuronal and humoral mechanisms may be involved. Brain H2 receptors appear to mediate some forms of endogenous analgesic response, especially those elicited by exposure to stressors [40]. Many of the modulatory actions of histamine discussed above appear to be activated as part of stress responses. For reasons that remain unclear, histamine releasers, such as thioperamide, show only mild, biphasic antinociceptive actions, even though histamine is a potent and effective analgesic substance.

Histamine may contribute to brain diseases or disorders

As mentioned above, a role for brain histamine in several neurodegenerative diseases, such as multiple sclerosis, Alzheimer's disease and Wernicke's encephalopathy, is being studied closely [3,12]. Whether from neurons or mast cells, histamine may participate in these processes by contributing to vascular changes, alterations in the blood—brain barrier, changes in immune function or even cell death. The ability of histamine to enhance excitatory transmission at NMDA receptors (discussed above) may explain its neurotoxic actions [3]. However, neuronal histamine does not always enhance brain damage; it seems to exert a protective effect in some models of cerebral ischemia. Histaminergic neurons are also activated by vestibular disturbances, leading to the release of histamine in brainstem emetic centers. Thus, neuronal histamine may be one mediator of motion sickness [41].

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Copyright © 1999, American Society for Neurochemistry.
Bookshelf ID: NBK28245


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