2.1 Histamine and histamine receptors in the brain
The histaminergic neuron is the main source of histamine production in the brain, whose soma is located in the tuberomammillary nucleus (TMN) of the hypothalamus. The histaminergic neuron fibers are widely distributed in the brain. Neuronal histamine is stored in cell somata and especially in axon varicosities (Haas, Sergeeva & Selbach, 2008). Besides neurons, one study found that cultured microglia also could synthesize histamine (Katoh et al., 2001), while the production of histamine in cerebrovascular endothelial cells is still controversial (Karlstedt et al., 1999; Yamakami et al., 2000). In the peripheral connective tissue, histamine is synthesized and released from mast cells and basophils, which is closely associated with immune response. Stomach enterochromaffin-like cells also give rise to the release of histamine to regulate gastric acid secretion. Interestingly, under some pathological conditions, mast cells can enter the brain. Distinct sources of histamine are shown in Fig.1.
The dietary amino acid L-histidine taken up into neurons by L-amino acid transporter was catalyzed by histidine-decarboxylase (HDC) into histamine by decarboxylation. Neuronal histamine was packaged into vesicles through vesicular monoamine transporter-2 (VMAT-2), and calcium release evokes histamine release from vesicles upon the histaminergic neuron depolarization (Erickson, Schafer, Bonner, Eiden & Weihe, 1996). Then neuronal histamine release into the postsynaptic cleft, which is metabolized into tele-methyhistamine by histamine N -methyltransferase (HNMT) and then degraded into Nl -methylimidazole acetic acid by monoamine oxidase B (Fig.1). Brain histamine modulates several physiological and pathological processes, including sleep-wake cycle, water and food intake, locomotion, neuroendocrine regulation, attention, learning and memory, epilepsy and so on (Sadek, Saad, Sadeq, Jalal & Stark, 2016).There are four histamine receptors have been identified in the brain: histamine H1, H2, H3, and H4 receptors (H1R, H2R, H3R, and H4R). H1R and H2R were postsynaptically located, H3R was both presynaptically and postsynaptically located. It is still controversial that whether H4R is expressed in neurons.