**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 (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 downstream of the H3 receptor.

Histaminergic Modulation of Body Temperature and Energy Expenditure 201

H1 → firing rate ↑

**Figure 1.** Simplified diagram of the neural pathways controlling thermoeffector mechanisms (Morrison and Nakamura, 2011). The diagram also illustrates the proposed cellular mechanisms activated by histamine. GABAergic neurons in the MnPOA tonically inhibit sympathetic premotor neurons in the rostral raphe pallidus. Histamine reduces the firing rates of GABAergic MnPO neurons. This results in stimulation of the sympathetic output system. Activation of H1 and H2 receptors expressed by MnPO and MPON neurons, respectively, increased firing rates and stimulates the sympathetic neuron system. The dashed lines indicate that the respective projections have been suggested by physiological studies

+

Rostral raphe pallidus (rRPA)

Ventral horn

Somatic nerve system

Sympathetic nerve system

+

+

Intermediolateral cell column (IML)

+

GLUT

Medial preoptic nucleus (MPON)

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

*The Department of Molecular and Integrative Neurosciences, The Scripps Research Institute,* 

This work was supported by the National Institutes of Health Grant NS060799.

but have not been demonstrated directly.

GABA

H3 → firing rate ↓

H2 → firing rate ↑

H1 → firing rate ↑

GLUT

**8. Conclusion** 

Median preoptic nucleus (MnPO)

neuronal networks.

**Author details** 

Iustin V. Tabarean

**Acknowledgement** 

*La Jolla, USA* 

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 H3 receptor subtypes, respectively.

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 rate of glutamatergic neurons that express H2Rs [60].

**Figure 1.** Simplified diagram of the neural pathways controlling thermoeffector mechanisms (Morrison and Nakamura, 2011). The diagram also illustrates the proposed cellular mechanisms activated by histamine. GABAergic neurons in the MnPOA tonically inhibit sympathetic premotor neurons in the rostral raphe pallidus. Histamine reduces the firing rates of GABAergic MnPO neurons. This results in stimulation of the sympathetic output system. Activation of H1 and H2 receptors expressed by MnPO and MPON neurons, respectively, increased firing rates and stimulates the sympathetic neuron system. The dashed lines indicate that the respective projections have been suggested by physiological studies but have not been demonstrated directly.
