The hypocretin/orexins (Hcrt/Orxs) are hypothalamic neuropeptides that regulate stress, addiction, feeding and arousal behaviors. They depolarize many types of central neurons and can increase [Ca²⁺]_i in some, including those of the dorsal raphe (DR) and laterodorsal tegmental (LDT) nuclei -two structures likely to contribute to the behavioural actions of Hcrt/Orx. In this study, we used simultaneous whole-cell and Ca²⁺-imaging methods in mouse brain slices to compare the Hcrt/Orx-activated current in DR and LDT neurons and to determine if it contributes to the Ca²⁺ influx evoked by Hcrt/Orx. We found Hcrt/Orx activates a similar noisy cation current which reversed near 0 mV in both cell types. Contrary to our expectation, this current did not contribute to the somatic Ca²⁺ influx evoked by Hcrt/Orx. In contrast, Hcrt/Orx enhanced the Ca²⁺ transients produced by voltage steps (-60 to -30mV) by ~30% even in neurons lacking an inward current. This effect was abolished by nifedipine, augmented by Bay-K and abolished by bisindolylmaleimide I. Thus, Hcrt/Orx has two independent actions: activation of noisy cation channels which generate depolarization; and activation of a PKC-dependent enhancement of Ca²⁺ transients mediated by L-type Ca²⁺ channels. Immunocytochemistry verified that both these actions occurred in serotonergic and cholinergic neurons indicating that Hcrt/Orx can function as a neuromodulator in these key neurons of the reticular activating system. Since regulation of Ca²⁺ transients mediated by L-channels is often linked to the control of transcriptional signaling, our findings imply that Hcrt/Orxs may also function in the regulation of long-term homeostatic or trophic processes.