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The Journal of Neuroscience, August 11, 2004, 24(32):7159-7166; doi:10.1523/JNEUROSCI.1027-04.2004

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Behavioral/Systems/Cognitive
Serotonergic Regulation of the Orexin/Hypocretin Neurons through the 5-HT_1A Receptor

Yo Muraki,^1 * Akihiro Yamanaka,^1,2,3 * Natsuko Tsujino,^1 * Thomas S. Kilduff,³ Katsutoshi Goto,¹ and Takeshi Sakurai^1,2

¹Department of Pharmacology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan, ²Exploratory Research for Advanced Technology Yanagisawa Orphan Receptor Project, Japan Science and Technology Corporation, Tokyo 135-0064, Japan, and ³Molecular Neurobiology Laboratory, SRI International, Menlo Park, California 94025

Both orexin and serotonin (5-HT) have important roles in the regulation of sleep-wakefulness, as well as in feeding behavior. We examined the effects of 5-HT on orexin/hypocretin neurons, using hypothalamic slices prepared from orexin/enhanced green fluorescent protein (EGFP) transgenic mice in which EGFP is expressed exclusively in orexin neurons. Patch-clamp recording from EGFP-expressing cells showed that 5-HT hyperpolarized all orexin neurons in a concentration-dependent manner. The response was inhibited by the 5-HT_1A receptor antagonist WAY100635. A 5-HT_1A receptor agonist, 8-hydroxy-2-(dl-N-propyl-amino)tetralin, also evoked hyperpolarization on orexin neurons with potency comparable with 5-HT. A low concentration of Ba²⁺ (30 µM) inhibited 5-HT-induced hyperpolarization. Single-channel recording revealed that the conductance of 5-HT-induced channel activity was 33.8 pS, which is in good agreement with that of the G-protein-coupled inward rectifier potassium channel (GIRK). Moreover, 5-HT_1A receptor-like immunoreactivity was observed on orexin neurons, and 5-HT transporter immunoreactive nerve endings are in close apposition to orexin neurons. Intracerebroventricular injection of the 5-HT_1A receptor-selective antagonist WAY100635 (100 ng) increased locomotor activity during the latter half of dark phase in wild-type mice but not in orexin/ataxin-3 mice in which orexin neurons are specifically ablated, suggesting that activation of orexin neurons is necessary for the WAY100635-induced increase in locomotor activity. These results indicate that 5-HT hyperpolarizes orexin neurons through the 5-HT_1A receptor and subsequent activation of the GIRK and that this inhibitory serotonergic input to the orexin neurons is likely to be important for the physiological regulation of this neuropeptide system.

Key words: orexin; hypocretin; serotonin; patch clamp; transgenic mouse; slice

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Received March 20, 2004; revised June 21, 2004; accepted June 22, 2004.

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