**8. Conclusion**

200 Hyperthermia

downstream of the H3 receptor.

H3 receptor subtypes, respectively.

rate of glutamatergic neurons that express H2Rs [60].

(ERK1/2) and was not dependent on synaptic activity. Single-cell reverse transcription-PCR analysis revealed expression of H3 receptors in the histamine responsive population of GABAergic MnPO neurons. Histamine applied in the MnPO nucleus induced a robust, long-lasting hyperthermia effect that was mimicked by H3 histamine receptor subtypespecific agonists [21]. We have also established that an increase in the A-type K+ current in GABAergic MnPO neurons in response to activation of H3 histamine receptors results in decreased firing rate and hyperthermia in mice [61]. The Kv4.2 subunit is required for these actions since Kv4.2-/- preoptic GABAergic neurons are not affected by histamine or H3 agonists. Moreover, Kv4.2-/- mice develop much reduced hyperthermias in response to histamine or H3 agonists. Dynamic clamp experiments demonstrate that enhancement of the A-type current by a similar amount to that induced by histamine is sufficient to mimic its robust effect on firing rates. These experiments reveal a central role played by the Kv4.2 subunit in histamine regulation of body temperature and its interaction with pERK1/2

Our studies have also established that a population of non-GABAergic MnPO preoptic neurons was depolarized, and their firing rate was enhanced by histamine acting at H1 subtype receptors [21]. In our experiments, activation of the H1R receptors was linked to the phospholipase C pathway and Ca2+ release from intracellular stores. This depolarization persisted in TTX or when fast synaptic potentials were blocked, indicating that it represents a postsynaptic effect. Single-cell reverse transcription-PCR analysis revealed the expression of H1 receptors in these putative glutamatergic cells. The inward current is activated in a Ca-dependent manner. At high histamine (20 µM) concentration the excitation elicited by histamine in glutamatergic MnPO neurons has also a persistent component that can last for at least 40 min after the removal of the bioamine. TRPC1 and TRPC5 channels appear to be the channels that contribute most to the inward current activated downstream of H1Rs. H1 agonists also induced long-lasting hyperthermia when injected intra-MnPO. These studies have shown that histamine modulates the core body temperature by acting at two distinct populations of preoptic neurons that express H1 and

The mechanisms activated by histamine in the MPON are different. Histamine activates H2 subtype receptors in the MPON and induces hyperthermia [60]. We also found that a population of glutamatergic MPON neurons express H2Rs and are excited by H2R specific agonists. The agonists decreased the input resistance of the neuron and increased the depolarizing "sag" observed during hyperpolarizing current injections. Activation of H2Rs induced an inward current that was blocked by ZD7288, a specific blocker of the hyperpolarization activated cationic current (Ih). In voltage-clamp experiments, activation of H2R receptors resulted in increased Ih amplitude in response to hyperpolarizing voltage steps and a depolarizing shift in its voltage-dependent activation. The neurons excited by H2 specific agonism expressed the HCN1 and HCN2 channel subunits. Our data indicate that at the level of the MPON histamine influences thermoregulation by increasing the firing Histamine has a complex influence on thermoregulation and its circadian cycle and appears to be involved in numerous pathophysiological responses that involve changes in core body temperature. At the level of the MnPO and MPON histamine induces potent hyperthermia and an increase in energy expenditure by activating several signaling pathways and neuronal networks.
