Direct and Indirect Inhibition by Catecholamines of Hypocretin/Orexin Neurons

Abstract

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 ϩ (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.

Orexin Neurons Are Directly and Indirectly Regulated by Catecholamines in a Complex Manner

“…In contrast, we and Li and van den Pol (2005) observed that mouse orexin neurons showed NAinduced hyperpolarization. To examine whether SD alters the response of mouse orexin neurons to NA, we performed calcium imaging using hypothalamic slices from orexin/YC2.1 transgenic mice in which orexin neurons specifically express calcium-sensing protein.…”

“…Previous studies have demonstrated that NA (Li et al 2002;Li and van den Pol 2005;Yamanaka et al 2003b) and DA (Yamanaka et al 2003b) show inhibitory effects on orexin neurons. The present study confirms these results, extends these observations to adrenaline and establishes that the hyperpolarization induced by catecholamines involves ␣ 2A -ARs and, subsequently, an activation of GIRK channels.…”

“…Elsewhere we showed that activation of 5-HT 1A receptors and G protein-activated inward rectifier potassium (GIRK) channels are involved in 5-HT-induced hyperpolariza-tion of orexin neurons (Muraki et al, 2004). Li and van den Pol (2005) reported that orexin neurons are inhibited by noradrenaline through ␣ 2 adrenergic receptors (␣ 2 -AR) and GIRK channels in mice. Recent reports using rats, however, showed an intriguing result that orexin neurons are activated by NA but are inhibited when rats were sleep deprived for a few hours (Bayer et al 2005;Grivel et al 2005).…”

The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems

“…Although it was unexpected that the LC and DR did not increase Fos expression in response to SD in VEH-treated animals, the mixed downstream effects of NE and generally inhibitory effects of 5HT on other wakepromoting cell groups (Brown et al, 2012;Li et al, 2002;Li and van den Pol, 2005) contrast with the excitatory effects of Hcrt, HA, and ACh on these groups , suggesting that the LC and DR may be differentially regulated. The elevated Fos expression observed in the LC following forced wakefulness in ZOL but not VEH or ALM treatment groups is also surprising considering the inhibitory effect of ZOL in other regions, but this may be a result of the greatly increased level of stimulation required to keep ZOLtreated rats awake during forced wakefulness coupled with the high sensitivity of Fos expression in the LC to stress (Sved et al, 2002).…”

Approaching the shared biology of obesity and depression: the stress axis as the locus of gene–environment interactions

“…78,79 While orexin activates catecholamines and endocannabinoids, catecholamines and serotonin exert a negative feedback on the orexin system. 80,81 These findings suggest a central role for the orexin systems in the shared biology of feeding and mood disorders.…”