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The Journal of Neuroscience, January 5, 2005, 25(1):173-183; doi:10.1523/JNEUROSCI.4015-04.2005
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Behavioral/Systems/Cognitive
Direct and Indirect Inhibition by Catecholamines of Hypocretin/Orexin Neurons
Ying Li and
Anthony N. van den Pol
Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520
Hypothalamic hypocretin enhances arousal, similar to the actions of norepinephrine (NE). The physiological actions of NE were examined in hypocretin neurons identified by selective green fluorescent protein expression in transgenic mouse hypothalamic slices using whole-cell recording. NE induced an outward current, inhibited spike frequency, and hyperpolarized hypocretin neurons dose dependently. Similar actions were evoked by the selective  2 adrenergic agonist clonidine. The 2 antagonist idazoxan increased spike frequency, suggesting tonic NE-mediated inhibition. The NE-induced current was inwardly rectified, and the reversal potential was dependent on external potassium concentration; it was blocked by barium in the bath and by GTP- -S in the pipette, suggesting activation of a G-protein inward rectifying K+ (GIRK) current. NE and clonidine decreased calcium currents evoked by depolarizing voltage steps. The selective 1 adrenergic agonist phenylephrine had no effect on membrane potential but did increase IPSC frequency; miniature IPSC frequency was also increased, in some cells without any effect on amplitude, suggesting a facilitative presynaptic action at 1 receptors on GABAergic axons that innervate hypocretin neurons. NE therefore inhibits hypocretin neurons directly through two mechanisms: activation of a GIRK current, depression of calcium currents, and indirectly through increased inhibitory GABA input. Similar to NE, dopamine and epinephrine reduced or blocked spikes and, in the presence of TTX, showed direct hyperpolarizing actions. The action of dopamine was blocked by the D2 receptor antagonist eticlopride, whereas a D1/5 antagonist had no effect. These data suggest that catecholamines evoke strong inhibitory actions on hypocretin neurons and suggest negative feedback from catecholamine cells that may be excited by hypocretin.
Key words: arousal; dopamine; patch clamp; sleep; lateral hypothalamus; norepinephrine; food intake
Received July 15, 2004;
revised November 9, 2004;
accepted November 10, 2004.
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