Histamine brain

In 1966, the name was proposed (5) for receptors blocked by the at that time known antihistamines. It was also speculated that the other actions of histamine were likely to be mediated by other histamine receptors. The existence of the H2 receptor was accepted in 1972 (6) and the receptor was recognized in rat brain in 1983 (7). receptors in the brain appear to be involved in the feedback control of both histamine synthesis and release, whereas release of various other neurotransmitters, eg, serotinin (5-HT), dopamine, noradrenaline, and acetylcholine, is also modulated (8) (see Neuroregulators). 

L-Tyrosine metabohsm and catecholamine biosynthesis occur largely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andhpid metabohsm. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bUe acids and the detoxification process of aromatic dmgs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabohsm related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

Although mast cells and basophils probably account for >90% of stored histamine in the body, histamine is also present in platelets, enterochromaffin-like cells, endothelial cells, and neurons. Histamine can act as a neurotransmitter in the brain. Histaminergic nerves have their cell bodies within a very small area of the brain (the magnocellular nuclei of the posterior hypothalamus) but have axons in most areas of the forebrain. There is also evidence for axons projecting into the spinal (Fig. 1) cord. Finally, there is evidence that histamine synthesis can be induced in tissues undergoing rapid tissue growth and repair. In certain neonatal tissues (e.g. liver), the rate of synthesis of this unstored diffusable histamine (termed nascent histamine) is profound and may point to a role for histamine is cell proliferation. 

Hi-receptors in the adrenal medulla stimulates the release of the two catecholamines noradrenaline and adrenaline as well as enkephalins. In the heart, histamine produces negative inotropic effects via Hr receptor stimulation, but these are normally masked by the positive effects of H2-receptor stimulation on heart rate and force of contraction. Histamine Hi-receptors are widely distributed in human brain and highest densities are found in neocortex, hippocampus, nucleus accumbens, thalamus and posterior hypothalamus where they predominantly excite neuronal activity. Histamine Hrreceptor stimulation can also activate peripheral sensory nerve endings leading to itching and a surrounding vasodilatation ( flare ) due to an axonal reflex and the consequent release of peptide neurotransmitters from collateral nerve endings. 

The two examples given here will be the determination of flavones in grapefruit juice and the measurement of histamine in rat brain. 

Chromatogram Showing Histamines from Rat Brain Tissue... 

After an overview of neurotransmitter systems and function and a consideration of which substances can be classified as neurotransmitters, section A deals with their release, effects on neuronal excitability and receptor interaction. The synaptic physiology and pharmacology and possible brain function of each neurotransmitter is then covered in some detail (section B). Special attention is given to acetylcholine, glutamate, GABA, noradrenaline, dopamine, 5-hydroxytryptamine and the peptides but the purines, histamine, steroids and nitric oxide are not forgotten and there is a brief overview of appropriate basic pharmacology. 

The belief that histamine (HT) has a central effect stems from the knowledge that all the classical antihistamines (Hi receptor antagonists) used to treat allergic reaction, such as hay fever, caused marked sedation if, like mepyramine and promethazine, they can cross the blood-brain barrier, but fail to do so if, like terfenedine and cetirizine, they do not. 

Histamine is synthesised by decarboxylation of histidine, its amino-acid precursor, by the specific enzyme histidine decarboxylase, which like glutaminic acid decarboxylase requires pyridoxal phosphate as co-factor. Histidine is a poor substrate for the L-amino-acid decarboxylase responsible for DA and NA synthesis. The synthesis of histamine in the brain can be increased by the administration of histidine, so its decarboxylase is presumably not saturated normally, but it can be inhibited by a fluoromethylhistidine. No high-affinity neuronal uptake has been demonstrated for histamine although after initial metabolism by histamine A-methyl transferase to 3-methylhistamine, it is deaminated by intraneuronal MAOb to 3-methylimidazole acetic acid (Fig. 13.4). A Ca +-dependent KCl-induced release of histamine has been demonstrated by microdialysis in the rat hypothalamus (Russell et al. 1990) but its overflow in some areas, such as the striatum, is neither increased by KCl nor reduced by tetradotoxin and probably comes from mast cells. 

Histamine receptors were first divided into two subclasses Hi and H2 by Ash and Schild (1966) on the basis that the then known antihistamines did not inhibit histamine-induced gastric acid secretion. The justification for this subdivision was established some years later when Black (see Black et al. 1972) developed drugs, like cimetidine, that affected only the histamine stimulation of gastric acid secretion and had such a dramatic impact on the treatment of peptic ulcers. A recently developed H2 antagonist zolantidine is the first, however, to show significant brain penetration. A further H3 receptor has now been established. It is predominantly an autoreceptor on histamine nerves but is also found on the terminals of aminergic, cholinergic and peptide neurons. All three receptors are G-protein-coupled but little is known of the intracellular pathway linked to the H3 receptor and unlike Hi and H2 receptors it still remains to be cloned. Activation of Hi receptors stimulates IP3 formation while the H2 receptor is linked to activation of adenylate cyclase. 

Pollard, H, Moreau, J, Arrang, JM and Schwartz, JC (1993) A detailed autoradiographic mapping of histamine H3 receptors in rat brain areas. Neuroscience 52 168-189. 

Russell, WL, Henry, DP, Phebus, LA and Clemens, JA (1990) Release of histamine in rat hypothalamus and corpus striatum in vivo. Brain Res. 512 95-101. 

Although histamine has mixed excitatory and inhibitory effects on central neurons, those antihistamines (Hi-receptor antagonists) that enter the brain produce sedation this indicates that the predominant overall effect of histamine is excitatory. The preferred explanation for this rests on evidence that histaminergic neurons in the posterior hypothalamus are active in waking and silent in deep SWS and REM sleep. 

D., Smith, 1. R., Sore, N. E., Wilks, T.. Development of a new physicochemical model for brain penetration and its application to the design of centrally acting H2 receptor histamine antagonists. J. Med. Chem. 1988, 31, 656-671. 

Although most of the medicinal chemistry effort in the H3 receptor field has been focused on the development of antagonists, there is some interest in agonists as well. Histamine H3 receptor agonists decrease the release of histamine in the central and peripheral nervous system and lead to a weakened histaminergic tone. In the brain, their effects will therefore be comparable to those of Hi receptor antagonists, with sedation and induction of sleep as a prominent observation. Indeed, H3 agonists such as the imidazoles... 

Motion sickness is caused by stimulation of the vestibular system. This area contains many histaminic (Hj) and muscarinic cholinergic receptors. The higher brain (i.e., cerebral cortex) is affected by sensory input such as sights, smells, or emotions that can lead to vomiting. This area is involved in anticipatory nausea and vomiting associated with chemotherapy. 

Histamine is synthesized in the brain from L-histidine by the enzyme histidine decarboxylase (HDC) (Fig. 2.2C). HDC can be inhibited by application of a-fluoromethylhistidine (a-FMH). Unlike serotonin and the catecholamines, no... 

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