Orexin/Hypocretin-1 Receptor Antagonism Selectively Reduces Cue-Induced Feeding in Sated Rats and Recruits Medial Prefrontal Cortex and Thalamus.

Sindy Cole,Gorica D Petrovich,Heather S Mayer

doi:10.1038/srep16143

Abstract

The orexin/hypocretin system is important for reward-seeking behaviors, however less is known about its function in non-homeostatic feeding. Environmental influences, particularly cues for food can stimulate feeding in the absence of hunger and lead to maladaptive overeating behavior. The key components of the neural network that mediates this cue-induced overeating in sated rats include lateral hypothalamus, amygdala, and medial prefrontal cortex (mPFC), yet the neuropharmacological mechanisms within this network remain unknown. The current study investigated a causal role for orexin in cue-driven feeding, and examined the neural substrates through which orexin mediates this effect. Systemic administration of the orexin-1 receptor (OX1R) antagonist SB-334867 had no effect on baseline eating, but significantly reduced cue-driven consumption in sated rats. Complementary neural analysis revealed that decreased cue-induced feeding under SB-334867 increased Fos expression in mPFC and paraventricular thalamus. These results demonstrate that OX1R signaling critically regulates cue-induced feeding, and suggest orexin is acting through prefrontal cortical and thalamic sites to drive eating in the absence of hunger. These findings inform our understanding of how food-associated cues override signals from the body to promote overeating, and indicate OX1R antagonism as a potential pharmacologic target for treatment of disordered eating in humans.

Highlights

Environmental and social factors critically control our appetites and food consumption
We showed that the orexin-1 receptor (OX1R) antagonist SB-334867 decreased food intake driven by a food cue selectively, with no effect on baseline eating
We found elevated Fos induction within the medial prefrontal cortex (mPFC) (PL and infralimbic area (ILA)) and PVTa in rats tested for cue-induced feeding under SB-334867, compared to rats tested under vehicle

Summary

Introduction

Environmental and social factors critically control our appetites and food consumption. Presentation of food- or reward-predictive cues alone is sufficient to strongly activate orexin neurons[11,12,13], suggesting a broader role for orexin in mediating reward-driven motivated behaviors. Consistent with this view, orexin receptor blockade significantly reduces self-administration for palatable foods in a variety of preparations. Systemic orexin blockade has been shown to reduce motivation to respond for high-fat pellets[17], and to decrease cue-induced reinstatement of sucrose- and saccharin-seeking behavior[15,16]. OX1R antagonism has attenuated operant responding for food pellets[25] and palatable, high-fat pellets[14], and prevented cue- and stress-induced reinstatement of sucrose-seeking[15,26]

Methods

Results

Conclusion