CRF system recruitment mediates dark side of compulsive eating

Abstract

Dieting to control body weight involves cycles of deprivation from palatable food that can promote compulsive eating. The present study shows that rats withdrawn from intermittent access to palatable food exhibit overeating of palatable food upon renewed access and an affective withdrawal-like state characterized by corticotropin-releasing factor-1 (CRF(1)) receptor antagonist-reversible behaviors, including hypophagia, motivational deficits to obtain less palatable food, and anxiogenic-like behavior. Withdrawal was accompanied by increased CRF expression and CRF(1) electrophysiological responsiveness in the central nucleus of the amygdala. We propose that recruitment of anti-reward extrahypothalamic CRF-CRF(1) systems during withdrawal from palatable food, analogous to abstinence from abused drugs, may promote compulsive selection of palatable food, undereating of healthier alternatives, and a negative emotional state when intake of palatable food is prevented.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Effects of the CRF1 receptor antagonist R121919 (−1 h pretreatment, 0, 5, 10, and 20 mg/kg, s.c.) on cumulative 3-h food intake in (A) P phase (upon renewed access to the palatable food), (B) C phase (when rats had been withdrawn from the palatable diet to chow), and (C) amplitude of cycling (the difference between P phase and C phase intakes after a history of alternating Chow/Palatable diet access in male Wistar rats; n = 20) (see Materials and Methods or Fig. S1 for diet schedule). R121919 increased chow intake and decreased palatable diet intake in Chow/Palatable rats with no effect in Chow/Chow rats. Rats were tested after seven cycles of diet alternation. Doses were given in a within-subjects design before the first chow day or before the first palatable day of four consecutive cycles, respectively. Panels show M± SEM. $$, P < 0.01, $$$, P < 0.001, linear contrast dose effect; #, P < 0.05, ##, P < 0.01, ###, P < 0.001, main dose effect; *, P < 0.05, **, P < 0.01, ***, P < 0.001, different from vehicle.

Fig. 2.

Effects of the CRF1 receptor antagonist R121919 (−1 h pretreatment, 0, 20 mg/kg, s.c.) on elevated plus-maze behavior (n = 47) and progressive-ratio responding for the less palatable food (n = 17) in male Wistar rats withdrawn from palatable food access. Rats were tested after 7 weeks of diet cycling. Panels show M ± SEM. (A) (Top) R121919 blocked the decrease in percentage of total arm time directed toward the open arms induced by withdrawing the highly palatable diet (less open arm time signifies more anxiogenic-like behavior). (Bottom) No effect was observed in the number of closed arm entries, an index of locomotor activity. (B) (Top Left) R121919 selectively blunted the deficits in breakpoint and (bottom left) total responses to obtain the less palatable chow in Chow/Palatable rats (lower scores signify hedonic-like deficit performance), without affecting performance of chow controls. (Right) Time-course of responding during the first 5 min. Inset shows the entire session (each symbol represents the mean number of cumulative reinforcers earned by subjects through that time point, irrespective of whether a subject had completed its session. The time course continued until each subject in the group stopped obtaining reinforcers). *, P < 0.05, **, P < 0.01, different from vehicle.

Fig. 3.

Effects of palatable diet alternation on (A) CRF mRNA and (B) CRF peptide expression in the central nucleus of the amygdala. Rats (n = 45) were diet-cycled for 7 weeks, and central nucleus of the amygdala punches were collected. Both CRF mRNA and peptide expression in the central nucleus of the amygdala of Chow/Palatable rats increased when the palatable diet was withdrawn (day 5) and returned to chow-fed control levels with access to the palatable diet (day 7). Panels show M± SEM. *, P < 0.05, **, P < 0.01, different from Chow/Chow.

Fig. 4.

Effects of the CRF1 receptor antagonist R121919 on GABAA-IPSPs in the central nucleus of the amygdala after a history of alternating palatable diet access in male Wistar rats (n = 14) withdrawn from palatable food access. (A) R121919 significantly decreased the amplitude of IPSPs across three stimulus intensities in Chow/Palatable rats compared with Chow/Chow rats. The dotted line represents the mean IPSP amplitude of cells from the respective diet group in the pressure of a CSF only. (B) Representative IPSP traces taken from a Chow/Chow rat (top) and a Chow/Palatable rat (bottom). Panels show M ± SEM. *, P < 0.05, **, P < 0.01, differs from Chow/Chow; #, P < 0.05, ###, P < 0.001, different from baseline (100%).