A Relationship between Reduced Nucleus Accumbens Shell and Enhanced Lateral Hypothalamic Orexin Neuronal Activation in Long-Term Fructose Bingeing Behavior

Abstract

Fructose accounts for 10% of daily calories in the American diet. Fructose, but not glucose, given intracerebroventricularly stimulates homeostatic feeding mechanisms within the hypothalamus; however, little is known about how fructose affects hedonic feeding centers. Repeated ingestion of sucrose, a disaccharide of fructose and glucose, increases neuronal activity in hedonic centers, the nucleus accumbens (NAc) shell and core, but not the hypothalamus. Rats given glucose in the intermittent access model (IAM) display signatures of hedonic feeding including bingeing and altered DA receptor (R) numbers within the NAc. Here we examined whether substituting fructose for glucose in this IAM produces bingeing behavior, alters DA Rs and activates hedonic and homeostatic feeding centers. Following long-term (21-day) exposure to the IAM, rats given 8–12% fructose solutions displayed fructose bingeing but unaltered DA D1R or D2R number. Fructose bingeing rats, as compared to chow bingeing controls, exhibited reduced NAc shell neuron activation, as determined by c-Fos-immunoreactivity (Fos-IR). This activation was negatively correlated with orexin (Orx) neuron activation in the lateral hypothalamus/perifornical area (LH/PeF), a brain region linking homeostatic to hedonic feeding centers. Following short-term (2-day) access to the IAM, rats exhibited bingeing but unchanged Fos-IR, suggesting only long-term fructose bingeing increases Orx release. In long-term fructose bingeing rats, pretreatment with the Ox1R antagonist SB-334867 (30 mg/kg; i.p.) equally reduced fructose bingeing and chow intake, resulting in a 50% reduction in calories. Similarly, in control rats, SB-334867 reduced chow/caloric intake by 60%. Thus, in the IAM, Ox1Rs appear to regulate feeding based on caloric content rather than palatability. Overall, our results, in combination with the literature, suggest individual monosaccharides activate distinct neuronal circuits to promote feeding behavior. Specifically, long-term fructose bingeing activates a hyperphagic circuit composed in part of NAc shell and LH/PeF Orx neurons.

Orexin/Hypocretin System: Role in Food and Drug Overconsumption

“…A role for the OX1R in mediating intake of palatable food is supported by the findings that systemic injection of the OX1R antagonist, SB-334867, reduces operant responding for both sucrose and saccharin pellets, in a minimal work paradigm with a fixed ratio 1 schedule (Cason & Aston-Jones, 2013a, 2013b, 2014). This antagonist also suppresses binge-like intake of sucrose, saccharin, and fructose solutions under an intermittent-access home cage drinking paradigm (Alcaraz-Iborra, Carvajal, Lerma-Cabrera, Valor, & Cubero, 2014; Rorabaugh, Stratford, & Zahniser, 2014) and reduces intake of a high-fat diet under both ad libitum and limited-access feeding paradigms (Choi, Davis, Fitzgerald, & Benoit, 2010; Valdivia, Patrone, Reynaldo, & Perello, 2014; White et al, 2005). Other OX1R antagonists similarly reduce intake of sweet-fat foods whether under ad libitum or intermittent-access feeding paradigms (Piccoli et al, 2012; Steiner, Sciarretta, Pasquali, & Jenck, 2013).…”

Differences in bingeing behavior and cocaine reward following intermittent access to sucrose, glucose or fructose solutions

“…Rats were singly housed with food (Teklad 2020X chow: 3.1 kcal/g, 24% protein, 16% fat, 60% carbohydrate; Harlan Laboratories, Denver, CO) and water available ad libitum for 5 days prior to commencing experiments. Rats were subsequently tested using the sugar bingeing model, as previously described (Avena et al, 2006a; Rorabaugh et al, 2014). At the onset of the experiment, rats continued to have 24-h access to an ad libitum water bottle but were cycled between 12 h of food deprivation and 12 h of access to chow and a second intermittent bottle that contained water (control; n=10), 8% sucrose, 8% glucose, or 8% fructose solution (0.29 kcal/mL; n=10/group).…”

“…Likewise, sucrose-bingeing rats show some of the neurochemical signs of DA hypersensitivity including elevated extracellular DA levels in response to sucrose intake, decreased DA D2 receptor (D2R) levels and increased DA transporter levels within the nucleus accumbens (NAc) (Bello et al, 2002; 2003; Rada et al, 2005; Avena et al, 2006b). Glucose-bingeing, but not fructose-bingeing, rats also display reduced D2R levels within the NAc (Colantuoni et al, 2001; Rorabaugh et al, 2014). A history of sucrose bingeing enhances locomotor responses to cocaine; however, whether bingeing on sucrose, or its components glucose and fructose, similarly alters the rewarding properties of cocaine has not been investigated.…”

“…a sugar binge, while water and chow intake remains unchanged (Rada et al, 2005; Avena et al, 2006b; Rorabaugh et al, 2014). The majority of sugar bingeing papers has used a 10% sucrose solution, although 25% glucose and 8–12% fructose solutions also produce bingeing behavior (Colantuoni et al, 2001; Avena and Hoebel, 2003; Gosnell, 2005; Rada et al, 2005; Avena et al, 2006a; Wojnicki et al, 2007; Rorabaugh et al, 2014). However, the wide range of sugar concentrations with varying caloric densities used in the different bingeing studies confound any direct comparisons between these three sugars.…”

Do Orexins contribute to impulsivity-driven binge consumption of rewarding stimulus and transition to drug/food dependence?

“…The OX antagonist SB-334867 inhibited the expression of conditioned place preference to high fat food when administered into the fourth ventricle (Kay et al, 2014) and decreased fructose consumption by rats in an Intermittent Access Model (IAM) that triggers binge-like consumption (Rorabaugh et al, 2014). A recent study showed that inhibiting the LH-VTA pathway reduces compulsive sucrose seeking but not food consumption in hungry mice, in a partial Reinforcement Sucrose-Retrieval Task (Nieh et al, 2015).…”