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The Journal of Neuroscience, August 10, 2005, 25(32):7459-7469; doi:10.1523/JNEUROSCI.1193-05.2005

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Behavioral/Systems/Cognitive
Cholecystokinin Activates Orexin/Hypocretin Neurons through the Cholecystokinin A Receptor

Natsuko Tsujino,^1 * Akihiro Yamanaka,^1,3 * Kanako Ichiki,¹ Yo Muraki,¹ Thomas S. Kilduff,⁴ Ken-ichi Yagami,² Satoru Takahashi,² Katsutoshi Goto,¹ and Takeshi Sakurai^1,3

¹Department of Molecular Pharmacology, Graduate School of Comprehensive Human Sciences, and ²Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan, ³Exploratory Research for Advanced Technology Yanagisawa Orphan Receptor Project, Japan Science and Technology Corporation, Tokyo 135-0064, Japan, and ⁴Molecular Neurobiology Laboratory, SRI International, Menlo Park, California 94025

Orexin A and B are neuropeptides implicated in the regulation of sleep/wakefulness and energy homeostasis. The regulatory mechanism of the activity of orexin neurons is not precisely understood. Using transgenic mice in which orexin neurons specifically express yellow cameleon 2.1, we screened for factors that affect the activity of orexin neurons (a total of 21 peptides and six other factors were examined) and found that a sulfated octapeptide form of cholecystokinin (CCK-8S), neurotensin, oxytocin, and vasopressin activate orexin neurons. The mechanisms that underlie CCK-8S-induced activation of orexin neurons were studied by both calcium imaging and slice patch-clamp recording. CCK-8S induced inward current in the orexin neurons. The CCK_A receptor antagonist lorglumide inhibited CCK-8S-induced activation of orexin neurons, whereas the CCK_B receptor agonists CCK-4 (a tetrapeptide form of cholecystokinin) and nonsulfated CCK-8 had little effect. The CCK-8S-induced increase in intracellular calcium concentration was eliminated by removing extracellular calcium but not by an addition of thapsigargin. Nifedipine, -conotoxin, -agatoxin, 4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride, and SNX-482 had little effect, but La³⁺, Gd³⁺, and 2-aminoethoxydiphenylborate inhibited CCK-8S-induced calcium influx. Additionally, the CCK-8S-induced inward current was dramatically enhanced in the calcium-free solution and was inhibited by the cation channel blocker SKF96365 suggesting an involvement of extracellular calcium-sensitive cation channels. CCK-8S did not induce an increase in intracellular calcium concentration when membrane potential was clamped at -60 mV, suggesting that the calcium increase is induced by depolarization. The evidence presented here expands our understanding of the regulation of orexin neurons and the physiological role of CCK in the CNS.

Key words: orexin; hypocretin; patch clamp; transgenic; cholecystokinin; CCK_AR

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Received March 28, 2005; revised July 4, 2005; accepted July 4, 2005.

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