Binge-eating is a central feature of bulimia nervosa and binge-eating disorder, which affect millions and renders many more susceptible to obesity and related diseases. Dieting and stress are well-known etiological factors of these disorders, and dieting is the strongest predictor of overeating in response to stress. However, the exact physiological mechanisms by which dieting and stress stimulate eating are not known. We have found that in rats, a history of cyclic food restriction (cFR), i.e. 'dieiting' alone or of stress from foot shock alone, does not alter food intake, but in rats with a history of cFR, stress produces powerful hyperphagia that is characteristic of binge-eating. This intake is marked by a strong preference for highly palatable (HP) food but can occur with regular food if triggered by a bite of HP food, it occurs in a discrete period of time, and while rats are sated. Using this model we propose to describe the physiology by which dieting and stress promote binge-eating. Our hypothesis is that cFR increases susceptibility to binge-eating by increasing two key orexigenic peptides, peptide YY (PYY) and opioids, and by suppressing key reward and satiety signals, namely dopamine receptors (R) in the nucleus accumbens and serotonin in the hypothalamus, respectively. These neuroadaptations to binge-eating develop in the course of repeated cFR. Stress then potentiates PYY and opioid signaling, possibly via corticosterone (CORT) modulation of these peptides, and magnifies an anhedonic state from desensitized dopamine-Rs. The animal binge-eats in response to unopposed orexigenic signals and as an attempt to restore normal levels of reward. To test this hypothesis we will measure hindbrain and hypothalamic concentrations of PYY and opioids and their modulation by CORT via radioimmunoassay. Gene expression of hypothalamic and accumbens opioid and dopamine-Rs will be quantified by RT-PCR, and extracellular levels of limbic dopamine and hypothalamic serotonin will be determined via high performance liquid chromatography. These measures will be determined in rats with a history of cFR after stress and compared to rats with a history of cFR alone, stress alone, or neither to understand how each of these factors contribute to the neurochemical adaptations that cause binge-eating. Finally we will test the effect of CORT, PYY-, and opioid-R blockade to reduce binge-eating and will manipulate access to HP food to evaluate its exact role in altering reward signaling. These experiments are critical to a complete understanding of the brain's control of food intake. By defining the neural substrates that mediate bingelike eating in this model, novel strategies that prevent, arrest, and reverse the disorder in humans can be tested.
