Although histaminergic neurones have not yet been histochemically visualized, there is little doubt that histamine (HA) has a neurotransmitter role in the invertebrate and mammalian central nervous system. For example, a combination of biochemical, electrophysiological and lesion studies in rats have shown that histamine is synthesized in and released from a discrete set of neurones ascending through the lateral hypothalamic area and widely projecting in the telencephalon. Histamine acts on target cells in mammalian brain via stimulation of two classes of receptor (H1 and H2) previously characterized in peripheral organs and probably uses Ca2+ and cyclic AMP, respectively, as second messengers. It is well established that several neurotransmitters affect neuronal activity in the central nervous system through stimulation not only of postsynaptic receptors, but also of receptors located presynaptically which often display distinct pharmacological specificity and by which they may control their own release. Such 'autoreceptors' have been demonstrated (or postulated) in the case of noradrenaline, dopamine, serotonin, acetylcholine and gamma-aminobutyric acid (GABA) neurones but have never been demonstrated for histamine. We show here that histamine inhibits its own release from depolarized slices of rat cerebral cortex, an action apparently mediated by a class of receptor (H3) pharmacologically distinct from those previously characterized, that is, the H1 and H2 receptors.

Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor.

Histamine is a transmitter in the nervous system and a signaling molecule in the gut, the skin, and the immune system. Histaminergic neurons in mammalian brain are located exclusively in the tuberomamillary nucleus of the posterior hypothalamus and send their axons all over the central nervous system. Active solely during waking, they maintain wakefulness and attention. Three of the four known histamine receptors and binding to glutamate NMDA receptors serve multiple functions in the brain, particularly control of excitability and plasticity. H1 and H2 receptor-mediated actions are mostly excitatory; H3 receptors act as inhibitory auto- and heteroreceptors. Mutual interactions with other transmitter systems form a network that links basic homeostatic and higher brain functions, including sleep-wake regulation, circadian and feeding rhythms, immunity, learning, and memory in health and disease.

Histamine in the Nervous System

The physiology of brain histamine.

A specific antiserum against histamine was produced in rabbits, and an immunohistochemical study of histamine-containing cells was carried out in rat brain. The antiserum bound histamine in a standard radioimmunoassay and stained mast cells located in various rat and guinea pig tissues. Enterochromaffin-like cells in the stomach and neurons in the posterior hypothalamic area could be detected with this antiserum. The staining was highly specific and was not abolished by preabsorption with histidine, histidine-containing peptides, serotonin, or catecholamines, whereas preabsorption with histamine completely abolished the staining. Immunoglobulins of this antiserum purified by affinity chromatography stained the same cells as did the crude antiserum, whereas the serum fraction, which was not absorbed by histamine-affinity ligand, failed to stain any neuron. Histamine-immunoreactive neuronal cell bodies were found only in the hypothalamic and premammillary areas of colchicine-treated rats. The largest group of cells was seen in the caudal magnocellular nucleus and medially on the dorsal and ventral aspects of the ventral premammillary nucleus. Immunoreactive nerve fibers, but no cell bodies, were detected in other parts of the brain. Histamine-immunoreactive mast cells were found in the median eminence and pituitary gland. The results suggest that histamine-containing neurons are located only in a small area of the posterior hypothalamus, and these cells are probably the source of ascending and descending fibers detected in other brain areas.

https://www.pnas.org/content/pnas/81/8/2572.full.pdf

Histamine-containing neurons in the rat hypothalamus.

Molecular Neurobiology of the Mammalian Brain

— The intraperitoneal administration of L-histidine in a dose of 1000 mg/kg increased threefold the whole brain levels of histamine in the mouse. This increase was evident in all brain regions except the medulla oblongata-pons. The subcellular localization of histamine and histidine was the same in mice administered bhistidine as in salinetreated animals. Cold exposure and restraint further augmented the elevation of histamine elicited by histidine treatment. a-Hydrazino-histidine and 4-bromo-3-hydroxybenzyloxyamine (NSD-1055) but not a-methyl-DOPA inhibited histidine decarboxylase [EC 4.1.1.221 activity in mouse brain homogenates and prevented the increase in brain histamine after histidine administration. NSD-1055 and a-hydrazino-histidine also lowered brain levels of histamine by 50 per cent. NSD-1055 lowered whole brain levels of histamine rapidly, with a half-life for the depletable histamine pool of about 5 min. Assuming that inhibition of histidine decarboxylase accounted for the reduction in histamine, then the rate of histamine decline reflects the rate of histamine turnover, and our results suggest that a portion of mouse brain histamine turns over quite rapidly. Reserpine lowered brain levels of histamine by about 50 per cent, whereas the antihistaminic agent, dexbrompheniramine, and sodium pentobarbital elevated histamine levels.

Dynamics of the regulation of histamine levels in mouse brain.

— We have examined the subcellular localization of histamine and histamine methyl-transferase (S-adenosylmethionine: histamine 7V-methyltransferase; EC 2.1.1.8) in rat brain. The highest levels of histamine and histamine methyltransferase activity were found in the hypothalamus. A large proportion of hypothalamic histamine and histamine methyltransferase activity was found in particles with sedimentation properties in sucrose gradients similar to synaptosomes storing norepinephrine and serotonin. Histamine displayed a bimodal distribution in sucrose gradients. A substantial amount of a tracer dose of [3H]histamine added to hypothalamic homogenates at 4°C was bound to particulate fractions, suggesting that endogenous histamine may redistribute and bind to subcellular fractions during homogenization. The second, lighter peak of histamine in sucrose gradients was thought to be due to histamine that redistributed during homogenization.

The subcellular localization of histamine and histamine methyltransferase in rat brain.

— The efflux of endogenous histamine from small slices of rat hypothalamus has been studied. Histamine release was temperature dependent and could be increased 50 % after depolarization of the brain slices by 15 mm potassium. The presence of EDTA in the incubating media inhibited the release of histamine and blocked the effect of potassium. Theophylline and reserpine markedly increased release of histamine, whereas phenoxybenzamine inhibited release and blocked the effects of theophylline and reserpine. Efflux of histidine from hypothalamic tissue slices was not temperature-dependent and was unaffected by the addition of potassium or any of the drugs studied.

K. M. Taylor

Papers

Dynamics of the regulation of histamine levels in mouse brain.

The subcellular localization of histamine and histamine methyltransferase in rat brain.

The release of histamine from tissue slices of rat hypothalamus.