**4. Histamine signaling in the brain**

Histamine is synthesized in the tuberomammilary nucleus (TMN) neurons from histidine by the specific enzyme histidine decarboxylase (HDC). After release histamine is methylated by histamine N-methyl-transferase (which is located postsynaptically and in glia). The turnover of neuronal histamine is high, with its half-life being ~ 30 min. The histaminergic TMN neurons project their axons throughout the brain and they control arousal, attention, energy expenditure, feeding, and thermoregulation. Histaminergic fibers are especially dense in the cortex, hypothalamus, amygdala and striatum (reviewed in [29]). In the hypothalamus the histaminergic fibers are particularly dense in the anterior part [30]. Another source of histamine in the brain is represented by resident mast cells [31].

Four histamine receptors, which are GPCRs, have been cloned (H1-H4R). The H1R, H2R and H3R are expressed in distinctive patterns in the brain [32] and all three receptor types are highly expressed in the hypothalamus. The H1Rs mediate excitatory actions on central neurons. At the cellular level, excitation is achieved by activation of Gq/11 and PLC, which leads to the formation of the two second messengers, diacylglycerol (DAG) and inositol-1,4,5-triphosphate (Ins(1,4,5)P3). Ins(1,4,5)P3 releases Ca2+ from internal stores, and this activates at least four Ca2+-dependent processes. First, the opening of a cation channel, which causes depolarization [33]. Second, activation of the electrogenic Na-Ca exchanger in supraoptic neurons, which also causes depolarization [34]. Third, formation of nitric oxide and cyclic GMP [35]. And finally, opening of K+ channels, resulting in hyperpolarization [36]. Furthermore, blocking a leak potassium conductance through direct G-protein action, or through PLC, DAG and PKC, can cause excitation in the thalamus [37], and in the striatum [38].

The H2Rs are coupled to Gs, adenylyl cyclase (AC) and PKA, which phosphorylates proteins and activates the transcription factor cyclic-AMP-response element (CRE)-binding protein (CREB). The direct action on neuronal membranes is usually excitatory or potentiates excitation. Like other transmitters that use this signaling pathway histamine blocks the small Ca2+-dependent K+ conductance ([39]). This conductance causes a long-lasting afterhyperpolarization and affects the accommodation of firing. A cortical neuron under active histaminergic input remains quiescent until it is reached by a sensory stimulus, which will then cause an enhanced and long-lasting response. Activation of H2Rs, by increasing cyclic AMP concentration, shifts the activation of the inwardly rectifying Ih towards a more positive voltage and contributes to a depolarization that modifies the thalamic relay of sensory input [37].

The H3Rs are located on histaminergic and other cell somata, dendrites and axons (varicosities), where they provide negative feedback to restrict histamine synthesis and release. They also provide negative feedback on the release of other transmitters, such as glutamate [40], acetylcholine and noradrenaline [41]. H3Rs are coupled to Gi/o and inhibit high voltage activated Ca2+ channels, a typical mechanism for the regulation of transmitter release. In rat, there are three functional splice variants of the H3R. In mouse, both RNase protection assay experiments and PCR results indicate that only one isoform of the H3R is present [42] which is coupled negatively to cAMP. H3Rs also activated the phospholipase A2 (PLA2) via the Gi/o proteins which results in production of arachidonic acid [43].

In summary, H1Rs and H2Rs have mostly excitatory actions on neurons or potentiate excitatory inputs. By contrast, H3-receptor activation causes autoinhibition of TMN neurons and inhibition of neurotransmitter release. Recent morphological and physiological studies suggest the presence of H3 receptors also postsynaptically [21,44,45].
