ΔFosB-Mediated Alterations in Dopamine Signaling Are Normalized by a Palatable High-Fat Diet

Background: Sensitivity to reward has been implicated as a predisposing factor for behaviors related to drug abuse as well as overeating. However, the underlying mechanisms contributing to reward sensitivity are unknown. We hypothesized that a dysregulation in dopamine signaling might be an underlying cause of heightened reward sensitivity whereby rewarding stimuli could act to normalize the system. Methods: We used a genetic mouse model of increased reward sensitivity, the ΔFosB-overexpressing mouse, to examine reward pathway changes in response to a palatable high-fat diet. Markers of reward signaling in these mice were examined both basally and following 6 weeks of palatable diet exposure. Mice were examined in a behavioral test following high-fat diet withdrawal to assess the vulnerability of this model to removal of rewarding stimuli. Results: Our results demonstrate altered reward pathway activation along the nucleus accumbens-hypothalamic-ventral tegmental area circuitry resulting from overexpression of ΔFosB in the nucleus accumbens and striatal regions. Levels of phosphorylated cyclic adenosine monophosphate (cAMP) response element binding protein (pCREB), brain-derived neurotrophic factor (BDNF), and dopamine and cyclic adenosine monophosphate regulated phosphoprotein with a molecular mass of 32 kDa (DARPP-32) in the nucleus accumbens were reduced in ΔFosB mice, suggestive of reduced dopamine signaling. Six weeks of high-fat diet exposure completely ameliorated these differences, revealing the potent rewarding capacity of a palatable diet. ΔFosB mice also showed a significant increase in locomotor activity and anxiety-related responses 24 hours following high-fat withdrawal. Conclusions: These results establish an underlying sensitivity to changes in reward related to dysregulation of ΔFosB and dopamine signaling that can be normalized with palatable diets and may be a predisposing phenotype in some forms of obesity.