**5. Central histaminergic modulation of core body temperature**

196 Hyperthermia

striatum [38].

sensory input [37].

PO/AH glutamatergic neurons [21].

**4. Histamine signaling in the brain** 

histamine in the brain is represented by resident mast cells [31].

send few local projections [28]. Our studies in mice have not found evidence for local projections of PO/AH GABAergic neurons but have revealed reciprocal connections of

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

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

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

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 The role of CNS histamine in thermoregulation has been established in various organisms from invertebrates [46] to lower vertebrates [47] as well as mammals. Early studies in mammals have reported a role of hypothalamic histamine in the control of body temperature [48]. The preoptic area/ anterior hypothalamus (PO/AH), region which contains temperature-sensitive neurons and regulates the thermoregulation setpoint, is the main locus in which histamine affects body temperature [49]. Histamine injected in the medial preoptic nucleus (MPON) induces hyperthermia. Similarly, intra-MPON injection of a histamine-N-methyltransferase inhibitor (which results in a local increase of histamine concentration) also produces hyperthermia [50]. Behavioral temperature selection studies suggest that preoptic histamine signaling affects both the set point of the hypothalamic thermostat, as well as heat loss mechanisms [51]. Both H1 and H2 receptors have been implicated in these responses.

Some studies suggest a hyperthermic tone due to histamine signaling. Thus, premedication with a H2R antagonist before general anesthesia augments core hypothermia during this procedure [52]. In pathological conditions histamine appears to mediate hypothermic responses. Ionizing radiation induces hypothermia that can be blocked by H1R and H2R antagonists applied centrally [53]. Exposure of the head to ionizing radiation appers to stimulate histamine release from brain-resident mast-cells [53].

Peripherally, histamine is involved in the rise of skin blood flow during whole body heating [54]. Similarly, combined H1R and H2R antagonists diminish the alcohol-induced flushing in individuals of Oriental origin [55].

More recent observations using transgenic models further indicate a role of histamine signaling in thermoregulation are. Thus H3R-/- transgenic mice display a lowered core body temperature suggesting that these receptors mediate a tonic hyperthermic action [56]. Other studies point to a hypothermic action of histamine, mediated by H1 subtype receptors. Thus, anaphylaxis induced hypothermia is not observed in HDC(-/-) mice or in the presence of H1R antagonists [57]. Also, IL-1β-induced thermogenesis is potentiated by depletion of hypothalamic histamine [58].

Our studies have established that in mice histamine induces hyperthermia when administered in either the medial or the median preoptic nuclei [59]. Similarly, when the endogenous concentration of histamine was raised in either nucleus by local injection of histamine *N*-methyl transferase inhibitor a hyperthermia of similar amplitude was observed [59]. H1R and H3R specific agonists were equally potent in inducing a hyperthermia when infused in the median preoptic nucleus [21]. In contrast, H2R specific agonists mimicked the histamine effect when administered intra-MPON, while H1R specific agonists had little effect [60]. Surprisingly, H3R specific agonists were without effect in this nucleus [60].

Histaminergic Modulation of Body Temperature and Energy Expenditure 199

decreased respiratory exchange ratio (RER). The hyperthermic effect is associated with a rapid increase in mRNA expression of uncoupling proteins in thermogenic tissues, the most pronounced being that of uncoupling protein (UCP) 1 in brown adipose tissue and of UCP2 in white adipose tissue. In diet-induced obese mice histamine had much diminished hyperthermic effects as well as reduced effect on RER. Similarly, the ability of preoptic histamine signaling to increase the expression of uncoupling proteins was abolished. We also found that the expression of mRNA encoding the H1 receptor subtype in the preoptic

Several H1R and H2R antagonists are clinically used in the treatment of several diseases. H1R antagonists (e.g. diphenhydramine hydrochloride, trade name Benadryl) are clinically used in the treatment of histamine-mediated allergic conditions. Clinically-relevant histamine H2R antagonists (e.g. ranitidine and cimetidine, trade names Zanatac and Tagamet, respectively) are used to reduce the secretion of gastric acid by acting on H2 receptors found principally in the parietal cells of the gastric mucosa. Interestingly, few side effects related to thermoregulation have been reported, due probably to the fact that these compounds cross the blood-brain barrier to a small extent. More recently, H3R antagonists have received a great interest from the pharmaceutical industry, with some drugs being in phase I or phase II of clinical trials [68]. Some projects have proposed H3R antagonists for the treatment of narcolepsy and/or cognitive disorders while others are trying H3R antagonists for the treatment of obesity and diabetes mellitus. All these drugs act at central H3Rs and produce increased levels of histamine in the brain, in particular in the hypothalamus. Since these compounds are designed to work centrally, the possibility of

H1R antagonists have been reported to increase seizure susceptibility in patients with febrile seizures [69,70]. These observations strengthen the idea that these drugs can act centrally to influence body temperature and other centrally regulated functions. Thus, H1R antagonists in most cases should not be prescribed to patients, particularly young infants, with febrile seizures and epilepsy. Drug-induced fever due to H2R blockers was also encountered, however the effect appears to be mediated by an allergic reaction to the drugs, characterized

**7. Cellular mechanisms involved in histamine induced hyperthermia** 

An early extracellular recording study found that most rat PO/AH neurons, irrespective to their thermosensitivities were excited by histamine, effect which was blocked by a H1 antagonist in most neurons [72]. In few neurons the excitation was blocked also by an H2 antagonist [72]. Our recent studies have revealed that histamine acts differentially on neurons of the median and medial preoptic nuclei (MnPO and MPON respectively). The neurotransmitter reduced the spontaneous firing rate of thermoregulatory GABAergic MnPO neurons by activating H3 subtype histamine receptors [21]. This effect involved a decrease in the level of phosphorylation of the extracellular signal-regulated kinase

area was significantly lower in obese animals [59].

thermoregulatory side effects is significantly enhanced.

by a marked increase in IgE [71].

Our experiments have also revealed that histamine modulation of the activity of GABAergic PO/AH neurons provides a mechanism for selective modulation of body temperature at the beginning of the active phase of the circadian cycle [61]. Thus, injection of a H3 antagonist in the MnPO induces a delay in the onset of the rise of the body temperature associated with the active phase of the circadian cycle [61].
