Role of orexin-1 receptor mechanisms on compulsive food consumption in a model of binge eating in female rats

Abstract

Orexins (OX) and their receptors (OXR) modulate feeding, arousal, stress, and drug abuse. Neural systems that motivate and reinforce drug abuse may also underlie compulsive food seeking and intake. Therefore, the effects of GSK1059865 (5-bromo-N-[(2S,5S)-1-(3-fluoro-2-methoxybenzoyl)-5-methylpiperidin-2-yl]methyl-pyridin-2-amine), a selective OX(1)R antagonist, JNJ-10397049 (N-(2,4-dibromophenyl)-N'-[(4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl]urea), a selective OX(2)R antagonist, and SB-649868 (N-[((2S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]-1-benzofuran-4-carboxamide), a dual OX(1)/OX(2)R antagonist were evaluated in a binge eating (BE) model in female rats. BE of highly palatable food (HPF) was evoked by three cycles of food restriction followed by stress, elicited by exposing rats to HPF, but preventing them from having access to it for 15 min. Pharmacokinetic assessments of all compounds were obtained under the same experimental conditions used for the behavioral experiments. Topiramate was used as the reference compound as it selectively blocks BE in rats and humans. Dose-related thresholds for sleep-inducing effects of the OXR antagonists were measured using polysomnography in parallel experiments. SB-649868 and GSK1059865, but not JNJ-10397049, selectively reduced BE for HPF without affecting standard food pellet intake, at doses that did not induce sleep. These results indicate, for the first time, a major role of OX(1)R mechanisms in BE, suggesting that selective antagonism at OX(1)R could represent a novel pharmacological treatment for BE and possibly other eating disorders with a compulsive component.

Figure 1

[³H]inositol phosphates (IPs) accumulation elicited by concentration–response curves (CRC) of orexin-A (OXA) (•) in rat basophil leukemia (RBL) cells expressing: rat OX₁R (rOX₁R) (a) in the presence of 1 (Δ), 3.3 (▾), 10 (⋄) and 33 μM (▪) of JNJ-10397049 or rOX₂R (b) in the presence of 10 nM (□), 3.3 nM (Δ), 0.1 μM (▾), 0.3 μM (⋄) of JNJ-10397049. The inset graph represents the Schild's linear regression analysis of rOX₂R data. Each point represents the mean±SEM of three independent experiments, each performed in duplicate.

Figure 2

[³H]inositol phosphates (IPs) accumulation elicited by concentration–response curves (CRC) of orexin-A (OXA) (•) in rat basophil leukemia (RBL) cells expressing: rOX₁R (a) in the presence of 0.3 (▴), 1 (▾), 3.3 (♦) and 10 nM (○) of GSK1059865 or rOX₂R (b) in the presence of 0.1 (□), 0.3 (Δ), 1 (▾), 3.3 μM (⋄) of GSK1059865. The inset graph represents the Schild's linear regression analysis of rOX₂R data. Each point represents the mean±SEM of three independent experiments, each performed in duplicate.

Figure 3

[³H]inositol phosphates (IPs) accumulation elicited by concentration–response curves (CRC) of orexin-A (OXA) (•) in rat basophil leukemia (RBL) cells expressing: rat rOX₁R (rOX₁R) (a) in the presence of 0.1 (□), 0.3 (Δ), 0.6 (▾), and 1 nM (▪) of SB-649868 or rOX₂R (b) in the presence of 0.1 (□), 0.3 (Δ), 1 (▾), and 3.3 nM (▪) of SB-649868. Each point represents the mean±SEM of three independent experiments performed in duplicate.

Figure 4

Effect of SB-649868 (1 and 3 mg/kg, by gavage) or its vehicle on highly palatable food (HPF) intake. Values are expressed as mean±SEM of nine rats. ^**P<0.01, difference from vehicle-treated rats; where not indicated, the difference was not statistically significant.

Figure 5

Effect of topiramate (60 mg/kg, by gavage) or its vehicle on highly palatable food (HPF) intake. Values are expressed as mean±SEM of nine rats. ^*P<0.05, difference from vehicle treated rats; where not indicated, the difference was not statistically significant.

Figure 6

Effect of JNJ-10397049 (1 and 3 mg/kg, intraperitoneally) (a) or GSK1059865 (10 and 30 mg/kg, by gavage) (b) on highly palatable food (HPF) intake. Values are expressed as mean±SEM of nine rats. ^*P<0.05, difference from vehicle-treated rats; where not indicated, the difference was not statistically significant.