Histamine hypothalamus

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. 

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 release in the hypothalamus is higher during the active waking than the quiescent phase of behaviour, whether this is associated with darkness (in rats) or light (rhesus monkey). The firing rate of histamine neurons is also higher during arousal... 

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. 

The histamine neurons in the tuberomammillary nucleus, in the posterior hypothalamus, project to the cortex and thalamus and receive an afferent input from... 

Figure 2.4 Flip-flop switch model of wake and slow wave sleep active systems. Mutually inhibitory connections exist between GABAergic/Galaninergic slow wave sleep active neurons in the ventrolateral preoptic area (VLPO) of the anterior hypothalamus and aminergic neurons in the hypothalamus (histamine (HA) neurons in the tuberomammillary nucleus (TMN)) and brainstem (serotonin (5-HT) neurons in the dorsal raphe (DR) and noradrenaline (NA) neurons in the locus coeruleus (LC)). Orexinergic neurons in the perifornical hypothalamus (PFH) stabilize the waking state via excitation of the waking side of the flip-flop switch (aminergic neurons).

John, J., Wu, M. F., Boehmer, L. N. Siegel, J. M. (2004). Cataplexy-active neurons in the hypothalamus implications for the role of histamine in sleep and waking behavior. Neuron 42, 619-4. 

Panula, P., Yang, H. Y. Costa, E. (1984). Histamine-containing neurons in the rat hypothalamus. Proc. Natl. Acad. Sci. USA 81, 2572-6. 

Histamine-containing neurons, located in the tuberomammillary nuclei (TMN) of the posterior hypothalamus, stimulate cortical activation through... 

Figure 6.2 The location and distribution of the histamine-containing neurons in the brain. These neurons are localized in the tuberomammiUaiy nucleus within the posterior hypothalamus and send projections throughout the brain. Abbreviations Hi, hippocampus Hy, hypothalamus IC, inferior colliculus OB, olfactory bulb SC, superior colliculus SI, substantia innominata St, striatum TH, thalamus TMN, tuberomammillary nucleus. Adapted from Watanabe Yanai (2001).

Figure 6.3 Histamine release measured from the posterior hypothalamus of freely behaving cats across the sleep-wakefulness cycle. The histamine release was higher during wakefulness compared with non-REM and REM sleep in each experiment, producing a highly significant group effect. Each experiment is represented by a single line (n = 5). Adapted from Strecker et al. (2002), to which the reader is referred for more details.

Ishizuka, T., Yamamoto, Y. Yamatodani, A. (2002). The effect of orexin-A and -B on the histamine release in the anterior hypothalamus in rats. Neurosci. Lett. 323, 93-6. 

Mochizuki, T., Yamatodani, A. Okakura, K. (1992). Chcadian rhythm of histamine release from the hypothalamus of freely moving rats. Physiol. Behav. 51,... 

Prast, H., Died, H. Philippu, A. (1992). Pulsatile release of histamine in the hypothalamus of conscious rats. J. Auton. Nerv. Syst. 39, 105-10. 

Reiner, P. B. McGeer, E. G. (1987). Electrophysiological properties of cortically projecting histamine neurons of the rat hypothalamus. Neurosci. Lett. 73,... 

Vanni-Mercier, G Gigout, S., Debilly, G. Lin, J. S. (2003). Waking selective neurons in the posterior hypothalamus and their response to histamine H3-receptor ligands an electrophysiological study in freely moving cats. Behav. Brain. Res. 

The neural structures involved in the promotion of the waking (W) state are located in the (1) brainstem [dorsal raphe nucleus (DRN), median raphe nucleus (MRN), locus coeruleus (LC), laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT), and medial-pontine reticular formation (mPRF)] (2) hypothalamus [tuberomammillary nucleus (TMN) and lateral hypothalamus (LH)[ (3) basal forebrain (BFB) (medial septal area, nucleus basalis of Meynert) and (4) midbrain ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) (Pace-Schott Hobson, 2002 Jones, 2003). The following neurotransmitters function to promote W (1) acetylcholine (ACh LDT/PPT, BFB) (2) noradrenaline (NA LC) (3) serotonin (5-HT DRN, MRN) (4) histamine (HA TMN) (5) glutamate (GLU mPRF, BFB, thalamus) (6) orexin (OX LH) and (7) dopamine (DA VTA, SNc) (Zoltoski et al, 1999 Monti, 2004). 

Some CNS stimulants have an effect on the same systems that are involved in wakefulness, including glutamate-, NE-, DA-, 5-HT-, histamine-, hypocretin- and ACh-containing neurons. This group includes molecules such as cocaine, amphetamine, and nicotine. The sleep-promoting systems are concentrated in the medial part of the brainstem, dorsal reticular substance of the medulla, anterior hypothalamus, and basal forebrain (Jones 2005). Other stimulants, such as caffeine and theophylline, block some sleep-inducing mechanisms. Modafinil is also a CNS stimulant with an unknown mechanism of action. 

Ookuma, K., Sakata, T., Fukagawa, K. etal. Neuronal histamine in the hypothalamus suppresses food intake in rats. Brain Res. 628 235-242,1993. 

Dopamine has an alerting effect. Neurochemicals involved in wakefulness include norepinephrine and acetylcholine in the cortex and histamine and neuropeptides (e.g., substance P and corticotropin-releasing factor) in the hypothalamus. 

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