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.