Eating 'Junk-Food' Produces Rapid and Long-Lasting Increases in NAc CP-AMPA Receptors: Implications for Enhanced Cue-Induced Motivation and Food Addiction

Abstract

Urges to eat are influenced by stimuli in the environment that are associated with food (food cues). Obese people are more sensitive to food cues, reporting stronger craving and consuming larger portions after food cue exposure. The nucleus accumbens (NAc) mediates cue-triggered motivational responses, and activations in the NAc triggered by food cues are stronger in people who are susceptible to obesity. This has led to the idea that alterations in NAc function similar to those underlying drug addiction may contribute to obesity, particularly in obesity-susceptible individuals. Motivational responses are mediated in part by NAc AMPA receptor (AMPAR) transmission, and recent work shows that cue-triggered motivation is enhanced in obesity-susceptible rats after 'junk-food' diet consumption. Therefore, here we determined whether NAc AMPAR expression and function is increased by 'junk-food' diet consumption in obesity-susceptible vs -resistant populations using both outbred and selectively bred models of susceptibility. In addition, cocaine-induced locomotor activity was used as a general 'read out' of mesolimbic function after 'junk-food' consumption. We found a sensitized locomotor response to cocaine in rats that gained weight on a 'junk-food' diet, consistent with greater responsivity of mesolimbic circuits in obesity-susceptible groups. In addition, eating 'junk-food' increased NAc calcium-permeable-AMPAR (CP-AMPAR) function only in obesity-susceptible rats. This increase occurred rapidly, persisted for weeks after 'junk-food' consumption ceased, and preceded the development of obesity. These data are considered in light of enhanced cue-triggered motivation and striatal function in obesity-susceptible rats and the role of NAc CP-AMPARs in enhanced motivation and addiction.

Figure 1

GluA1, but not GluA2, surface expression is greater in Junk-Food-Gainers than Non-Gainers. (a) Junk-food produces substantial weight gain in a subset of susceptible rats. (b) Eating junk-food followed by junk-food deprivation is associated with a sensitized response to cocaine in Junk-Food-Gainers (JF-G) compared with Junk-Food-Non-Gainers (JF-N). Inset shows locomotion during habituation and after saline injection. (c) Representative blot of GluA1 expression in crosslinked NAc samples. (d, e) GluA1, but not GluA2, surface expression is greater in Junk-Food-Gainers compared with Junk-Food-Non-Gainers after junk-food deprivation, suggesting the presence of CP-AMPARs. All data are shown as mean±SEM; *p<0.05.

Figure 2

The contribution of CP-AMPARs is greater in Junk-Food-Gainer vs chow-fed rats following junk-food deprivation. (a) Normalized amplitude before (BL) and after bath application of the CP-AMPAR antagonist naspm (200 μM). Inset shows example eEPSCs before (black) and after naspm (red). (b) The reduction by naspm is greater in Junk-Food-Gainer vs chow-fed rats. (c) Location of whole-cell recordings for all experiments. The shaded area indicates the general location of recordings made in the NAc core. Recordings fell approximately between 2.04 and 1.56 mm from Bregma; figure adapted from Paxinos and Watson (2007). All data shown as mean±SEM; *p<0.05. A full color version of this figure is available at the Neuropsychopharmacology journal online.

Figure 3

The relative abundance of NAc GluA1 surface vs intracellular (S/I) protein expression is enhanced after junk-food consumption and deprivation only in obesity-prone rats. This was due to shifts in both surface and intracellular protein expression. (a) Surface to intracellular ratio, (b) surface and (c) intracellular expression of GluA1 protein in obesity-resistant (OR) and obesity-prone (OP) rats given chow or junk-food. All data shown as mean±SEM; *p<0.05: OP-JF vs OP-Chow.

Figure 4

Just 10 days of junk-food followed by 2 weeks of junk-food deprivation is sufficient to induce CP-AMPAR upregulation in obesity-prone but not obesity-resistant rats. This increase occurred in the absence of differences in food intake and weight gain. (a) Normalized amplitude before and after naspm (200 μM). Inset: Example of eEPSCs from junk-food fed rats before (black) and after naspm (red). (b) Time course of eEPSC before and after naspm application. (c) The reduction by naspm is increased after junk-food in obesity-prone but not obesity-resistant rats. (d) Weight gain is similar between groups. (e) Junk-food consumption is similar between groups. All data shown as mean±SEM. *p<0.05; ***p<0.001 OP-JF vs all other groups. A full color version of this figure is available at the Neuropsychopharmacology journal online.

Figure 5

Junk-food-induced increases in CP-AMPARs are present after just 1 day of junk-food deprivation in obesity-prone but not obesity-resistant rats. (a) Normalized amplitude before (Baseline) and after naspm (200 μM). Inset: Example eEPSCs from junk-food fed rats before (black) and after naspm (red). (b) Time course before and after naspm application. (c) The reduction by naspm is greater in obesity-prone vs obesity-resistant rats given junk-food. (d) Weight gain is similar between groups. (e) Junk-food consumption is similar between groups. All data are shown as mean±SEM. * = p<0.05, **p<0.01. (f) Summary of individual eEPSC amplitudes across all studies (BL=baseline, N= + naspm; open symbols=chow groups, closed symbols=junk-food groups, triangles=outbred rats, circles=obesity-resistant rats, and squares=obesity-prone rats). A full color version of this figure is available at the Neuropsychopharmacology journal online.