Conclusions

In summary, our recent studies indicate that Hcrt/Orx peptides excite mesopontine cholinergic and non-cholinergic neurons of the LDT via multiple actions that are likely to have a powerful impact on their activity and integrative properties. Application of Hcrt/Orx causes sufficient depolarization of LDT neurons to drive even quiescent neurons into repetitive firing. This drive is mediated, at least partly, by activation of a noisy cation current and by excitation of presynaptic glutamate-releasing afferents. In contrast, Hcrt/Orx effects on presynaptic inhibitory afferents were more diverse. This may reflect a less important influence of Hcrt/Orx on inhibitory inputs or, more likely, may indicate that subpopulations of LDT neurons are differentially regulated by Hcrt/Orx.

Hcrt/Orx also produces a long-lasting increase in intracellular calcium in LDT neurons that arises from a calcium influx, mediated in part through L-type calcium channels rather than by release from intracellular stores or through reverse operation of the Na+/Ca2+ exchanger. Based on simultaneous whole-cell recording and calcium imaging, the cation current appears to contribute surprisingly little to the Hcrt/Orx-evoked calcium influx. Rather, it appears the cation current provides the depolarizing drive necessary to activate voltage-operated calcium-permeable channels, including L-type channels. These calcium channels, themselves appear to be up-modulated by Hcrt/Orx, perhaps through activation of PKC.45

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