The orexin₁ receptor antagonist SB-334867 dissociates the motivational properties of alcohol and sucrose in rats

Abstract

A role for orexin A in mediating the primary and conditioned reinforcing effects of alcohol has been established. It is unclear however whether the contribution of orexins to alcohol reward occurs independently of effects on appetite and feeding, and whether orexins regulate the motivation to consume alcohol compared to other rewards. To examine this further here we investigate the effect of the orexin₁ receptor antagonist, SB-334867, on self-administration of alcohol (10% v/v) under both fixed (FR) and progressive ratio (PR) schedules of reinforcement, and whether this differs from the motivation to administer a natural food reward, sucrose (0.2–0.7% w/v) in alcohol preferring (iP) rats. SB-334867 treatment significantly reduced responding for both alcohol and sucrose under a FR3 schedule; however, at the same dose, reduced responding and break point for ethanol, but not sucrose, under a PR schedule. These findings for the first time implicate a role for orexins in the motivation to self-administer alcohol and suggest that this may occur independent of any generalized effect on appetitive drive.

Introduction

Orexinergic neurons originate in the hypothalamus and project widely throughout the neuraxis to areas associated with reward, learning and memory, emotion and attention (Peyron et al., 1998). While these neuropeptides are classically involved in a range of homeostatic mechanisms including arousal and feeding (de Lecea et al., 1998), their anatomic distribution suggests that they may contribute to reward processing. Indeed a large volume of literature has recently identified a role, particularly for orexin A, in aspects of motivation and reward of drugs of abuse and natural reinforcers (reviewed in Cason et al., 2010, Lawrence, 2010, Thompson and Borgland, 2010).

In particular, orexin A has been implicated in mediating both the primary and conditioned reinforcing effects of alcohol reward. Studies have demonstrated that central orexin A administration can selectively increase ethanol consumption (Schneider et al., 2007) while orexin₁ receptor antagonists reduce ethanol intake in both operant self-administration (Lawrence et al., 2006, Richards et al., 2008) and two-bottle free choice (Moorman and Aston-Jones, 2009) paradigms in rats. Orexin₁ receptor blockade has also been shown to essentially inhibit both stress and cue-induced reinstatement of previously extinguished alcohol-seeking (Jupp et al., 2011, Lawrence et al., 2006, Richards et al., 2008) and exposure to cues and contexts associated with alcohol availability activates orexinergic neurons within the lateral hypothalamus (Dayas et al., 2008, Hamlin et al., 2007). More recently, it has been shown that acute alcohol can increase the expression of orexin A mRNA and mature peptide in this region (Morganstern et al., 2010). Another study however found that blockade of orexin A signaling had mixed effects on the acquisition and expression of a conditioned place preference to ethanol in mice (Voorhees and Cunningham, 2011). In addition, a role for orexins in alcohol drinking, but not seeking, has been suggested (Dhaher et al., 2010). Given this, it is unclear whether the putative role of orexins in alcohol reward occurs independently from effects on feeding related systems. Further, whether orexins also play a role in the motivational aspects of alcohol consumption remains unknown. To further investigate these aspects, here we report a study investigating the effects of orexin₁ receptor antagonism on the motivation to consume both alcohol and sucrose under a progressive ratio (PR) schedule of reinforcement. The results of this study for the first time demonstrate a role for orexinergic signaling in the motivation to self-administer alcohol but not sucrose suggesting that the role of orexins in the motivation to consume ethanol may occur independent from a generalized impact on appetitive drive.