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This Article Full Text Full Text (PDF) All Versions of this Article: 100/4/2265    most recent 01388.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kohlmeier, K. A. Articles by Leonard, C. S. PubMed PubMed Citation Articles by Kohlmeier, K. A. Articles by Leonard, C. S.

Dual Orexin Actions on Dorsal Raphe and Laterodorsal Tegmentum Neurons: Noisy Cation Current Activation and Selective Enhancement of Ca²⁺ Transients Mediated by L-Type Calcium Channels

Department of Physiology, New York Medical College, Valhalla, New York

Submitted 21 December 2007; accepted in final form 23 July 2008

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 behavioral 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 whether it contributes to the Ca²⁺ influx evoked by Hcrt/Orx. We found Hcrt/Orx activates a similar noisy cation current that 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 –30 mV) 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 that generate depolarization and activation of a protein kinase C (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. Because 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.