Mu opioid receptor antagonism in the nucleus accumbens shell blocks consumption of a preferred sucrose solution in an anticipatory contrast paradigm

Highlights

• Anticipatory contrast models food choice and excessive consumption occurring in binge eaters.

• Opioid antagonists in the nucleus accumbens shell reduce intake of preferred sucrose solutions.

• Opioid signaling may contribute to patterns of food choice that increase the risk of binge eating.

Abstract

Binge eating, a central feature of multiple eating disorders, is characterized by excessive consumption occurring during discrete, often brief, intervals. Highly palatable foods play an important role in these binge episodes – foods chosen during bingeing are typically higher in fat or sugar than those normally consumed. Multiple lines of evidence suggest a central role for signaling by endogenous opioids in promoting palatability-driven eating. This role extends to binge-like feeding studied in animal models, which is reduced by administration of opioid antagonists. However, the neural circuits and specific opioid receptors mediating these effects are not fully understood. In the present experiments, we tested the hypothesis that endogenous opioid signaling in the nucleus accumbens promotes consumption in a model of binge eating. We used an anticipatory contrast paradigm in which separate groups of rats were presented sequentially with 4% sucrose and then either 20% or 0% sucrose solutions. In rats presented with 4% and then 20% sucrose, daily training in this paradigm produced robust intake of 20% sucrose, preceded by learned hypophagia during access to 4% sucrose. We tested the effects of site-specific infusions of naltrexone (a nonspecific opioid receptor antagonist: 0, 1, 10, and 50 μg/side in the nucleus accumbens core and shell), naltrindole (a delta opioid receptor antagonist: 0, 0.5, 5, and 10 μg/side in the nucleus accumbens shell) and beta-funaltrexamine (a mu opioid receptor antagonist: 0 and 2.5 μg/side in the nucleus accumbens shell) on consumption in this contrast paradigm. Our results show that signaling through the mu opioid receptor in the nucleus accumbens shell is dynamically modulated during formation of learned food preferences, and promotes binge-like consumption of palatable foods based on these learned preferences.

Introduction

Binge eating is a behavioral abnormality characterized by excessive consumption occurring during brief periods, often accompanied by feelings of loss of control (American Psychological Association, 2000). It is a hallmark of several eating disorders including bulimia and binge eating disorder (Miller and Golden, 2010). Binge eating is also associated with obesity and may importantly contribute to excessive weight gain (Spitzer et al., 1992). Neural mechanisms underlying binges are poorly understood and undoubtedly multifactorial in their origins, with changes in neural signaling underlying stress, reward, and motivation likely contributing (Adam and Epel, 2007, Davis et al., 2009). Food selection during binges, however, suggests an important role for neural circuits that promote hedonically driven feeding in binge eating. Foods eaten during binges are often higher in fat and sugar than those typically consumed and often include dessert and/or snack foods (Yanovski et al., 1992). Thus dissecting function in reward circuits promoting consumption of highly palatable foods may be particularly relevant to elucidating neural mechanisms underlying eating disorders as well as weight gain leading to obesity.

Opioid signaling in the nucleus accumbens (NAcc) has been strongly implicated in the control of food intake. Several lines of evidence suggest that mu opioid receptor (MOR) signaling in the NAcc selectively promotes hedonically driven feeding. First, stimulation of MORs in the NAcc increases consumption of palatable sweet and fatty foods, and blockade of opioid signaling decreases intake of these foods (Kelley et al., 1996, Kelley et al., 2002). However, MOR stimulation or blockade has more modest effects on consumption of hedonically neutral substances, such as water or standard rat chow (Zhang and Kelley, 1997, Zhang and Kelley, 2002, Lenard et al., 2010). Second, infusion of the MOR-specific agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) into the NAcc increases positive taste reactivity displays in response to intraoral infusion of a sucrose solution and can increase licking bout duration in rats consuming sweet or fatty solutions; previous work has shown that these measures are correlated with the palatability of the tastant consumed (Pecina and Berridge, 2000, Taha et al., 2009, Katsuura et al., 2011). Conversely, infusion of the MOR antagonist beta-funaltrexamine (beta-FNA) decreases positive taste reactivity (Shin et al., 2010). Third, in rats that are offered a choice of food pellets identical in macronutrient content but differing in flavor, NAcc MOR stimulation selectively increases consumption of the preferred flavor (Woolley et al., 2006). Fourth, MOR stimulation in the NAcc increases consumption of non-caloric sweet (Zhang and Kelley, 2002) and fatty (Katsuura et al., 2011) substances, demonstrating that rewarding orosensory taste and texture cues are sufficient for DAMGO-induced hyperphagia.

MOR signaling in the NAcc thus plays an important role in palatability-driven consumption under normal conditions. Studies in rodent models of binge eating suggest this role extends to (and possibly plays an even larger role in) excessive, binge-like consumption. Opioid antagonists have been consistently reported to decrease consumption in a variety of rodent models that emphasize distinct aspects of binge eating. Thus, systemic administration of naltrexone decreases intake in rats offered limited, intermittent access to fat and/or sucrose (Rao et al., 2008, Corwin and Wojnicki, 2009, Wong et al., 2009); systemic administration of the nonspecific opioid antagonist naloxone potently and selectively decreases binge-like intake produced by cycles of food restriction, stress, and palatable food access (Boggiano et al., 2005); and systemic naltrexone (Taha et al., 2006), nalmefene (a mu and kappa opioid receptor antagonist; Cottone et al., 2008) and GSK1521498 (a MOR inverse agonist; Giuliano et al., 2012) decrease binge-like consumption in an anticipatory contrast paradigm, which has been proposed to model qualitative aspects of food restriction contributing to binge eating (Cottone et al., 2008).

Despite existing evidence of an important role for endogenous opioid signaling in promoting binge-like eating, little is known about the specific brain circuits which contribute to this behavior, as most previous studies of opioid antagonists in relevant animal models have made use of systemic drug administration. In the present study, we tested the effects of opioid antagonist infusion into the NAcc core and shell to assess the contribution of opioid signaling in these brain regions to consumption occurring in an anticipatory contrast paradigm. The anticipatory contrast paradigm models binge-like consumption occurring during access to a preferred, highly palatable tastant. In addition, expectation of this tastant results in learned hypophagia for a less preferred alternative. Mechanisms underlying this learned hypophagia may be particularly relevant to understanding patterns of dietary selection in binge eaters that favor consumption of highly palatable foods over less palatable but perhaps healthier alternatives and thus serve to perpetuate binge eating (Waters et al., 2001, Cottone et al., 2008, Siega-Riz et al., 2008). Our results demonstrate that MOR signaling in the NAcc shell changes in concert with learned food preferences, and promotes binge-like intake of a preferred sucrose solution.