The brain stores and releases histamine from more than one type of cell

Mast cells are a family of bone marrow-derived secretory cells that store and release high concentrations of histamine. They are known to be present within and surrounding the brain of many species [1,2]. In many, but not all, species they are prevalent in the thalamus and hypothalamus, as well as in the dura mater, leptomeninges and choroid plexus [1]. The quantitative contribution made to brain histamine concentrations by mast cells can be substantial in some cases, such as rat thalamus, although various approaches to this problem have not reached the same conclusion. Earlier biochemical studies suggested that histamine in brain mast cells could be distinguished from neuronal histamine by characteristics such as histamine turnover rates, subcellular fractionation and ontogenic pattern [2]. However, activated mast cells may not show a slow histamine turnover rate. Brain and dural mast cells have been characterized histologically and histochemically in detail. Characterization of neuronal histamine has been facilitated by the study of mast cell-deficient mice and rats.

The functions for brain and dural mast cells are not certain, but several hypotheses are being investigated. The close proximity of many of these cells to blood vessels, along with the potent vascular actions of their contents, has led to the suggestion that they regulate blood flow, permeability and/or immunological access to the brain. Dural mast cells are localized in close proximity to sensory nerve fibers and may modulate the release of inflammatory mediators from these cells (see also H₃ receptor section and Table 14-1). Perhaps most intriguing are recent findings showing that behavioral and hormonal alterations can induce dramatic changes in the morphology or distribution of CNS mast cells. Brain and/or dural mast cells may also participate in neurodegenerative diseases, such as multiple sclerosis, Alzheimer's disease or Wernicke's encephalopathy [3,3a]. In addition to mast cells and neurons, other brain cells, such as cerebrovascular endothelial cells [2,4], may synthesize and/or store histamine.

Table 14-1

Interactions Between Histamine and Other Transmitters in the CNS.

Histaminergic fibers originate from the tuberomammillary region of the posterior hypothalamus

The inability to visualize histaminergic neurons greatly limited the understanding and acceptance of this neuronal system. In 1984, antibodies raised against histamine [5] or its biosynthetic enzyme [6] provided the first detailed anatomical studies of these cells and their distribution. In all mammals studied, including humans, histaminergic neurons are found in the tuberomammillary nucleus of the posterior basal hypothalamus (Fig. 14-2). In the rat brain, five cell clusters have been distinguished, termed E1–E5 [7], although this subdivision does not easily apply to other species.

Figure 14-2

The histaminergic system of the rat brain. A: Frontal sections through the posterior hypothalamus showing the location of histaminergic neurons and the designation of the E1–E5 subgroups. Arc, arcuate nucleus; DM, dorsomedial hypothalamic nucleus; (more...)

Histaminergic neurons have morphological and membrane properties that are similar to those of neurons storing other biogenic amines

Histaminergic perikarya can be of medium size, but most are large, bipolar or multipolar cells, with diameters of up to 30 μm. Ultrastructural characteristics resemble those of noradrenergic and serotonergic cell bodies [2]. Some of the most ventrally located cells may make direct contact with CSF.

Electrophysiological properties of histaminergic neurons, which have been characterized in both hypothalamic explants and brain slices, show spontaneous activity of about 2 Hz, positive action potentials, a persistent sodium current and both inward and transient outward rectification [8]. Noradrenergic and serotonergic neurons show similar properties.

Histaminergic fibers project widely to most regions of the central nervous system

Two ascending and at least one descending efferent pathways account for the histaminergic innervation of the mammalian brain and spinal cord (Fig. 14-2B). The ascending tracts are predominantly, 70 to 80%, ipsilateral. All cell groups appear to contribute to all pathways. Although nearly all CNS areas contain some histaminergic fibers, the density of innervation is heterogeneous [9,10]. The highest densities are found in several hypothalamic nuclei, the medial septum, the nucleus of the diagonal band and the ventral tegmental area. Moderate densities are found in cerebral cortex, amygdala and basal ganglia. Most areas of the brainstem and spinal cord contain only small numbers of fibers. These densities follow closely the tissue concentrations of histamine and its biosynthetic enzyme found throughout the brain [11]. In the monkey brain, a homogeneous innervation of many areas of the visual system has also been noted. Ultrastructural studies in rat show that histaminergic varicosities form only a few synaptic contacts, implying that most neuronal histamine is released by nonsynaptic mechanisms; this seems to be the case for the other amine transmitter systems as well. However, histaminergic synapses have been characterized in some detail in rat brain, such as in the innervation of the mesencephalic trigeminal nucleus. Histaminergic varicosities also appear to make contact with glia and blood vessels [7].

A number of substances are colocalized with histamine and its biosynthetic enzyme in hypothalamic tuberomammillary neurons [12]. These include glutamate decarboxylase (GAD), GABA, GABA-transaminase (GABA-T), adenosine deaminase, monoamine oxidase-B (MAO-B) and the neuropeptide Met-Enk-Arg⁶-Phe⁷. A subset of cells in rat brain also contain galanin. Thyrotropin-releasing hormone (TRH) is present in some rat histaminergic neurons but is absent from those in mouse and guinea pig. These findings suggest that some of these peptides, as well as GABA and/or adenosine, may function as cotransmitters in this system. Galanin may be a presynaptic inhibitor of neuronal histamine release, similar to its proposed actions on cholinergic and serotonergic fibers. Endogenous GABA appears to regulate neuronal histamine release, but the cellular origin of this GABA is not known (Table 14-1).

Relatively little is known about the afferent connections to the histaminergic tuberomammillary neurons. Double-labeling experiments suggest that these cells receive innervation from the infralimbic prefrontal cortex, several areas within the septum/diagonal band complex and the medial preoptic area of the hypothalamus. These or other afferents seem to contain neuropeptide Y (NPY) or substance P. Other experiments suggest that tuberomammillary cells may also receive monoaminergic input from adrenergic (C1–C3), noradrenergic (A1–A2) and serotonergic (B5–B9) cells. Since some of these areas seem to have both input and output connections with histaminergic areas, the possibility of reciprocal control has been considered [2].

Histaminergic neurons are present in many species

Histaminergic neurons have been detected in the hypothalamus or diencephalon in a variety of vertebrate brains, including those of fish, snake, turtle and bird. In invertebrates, histamine also seems to function as a transmitter, for example, in arthropod and insect photoreceptors [13,14,14a]. It is well established that the C2 neuron of Aplysia uses histamine as a transmitter [15].