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Delta FosB-mediated alterations in dopamine signaling are normalized by a palatable high-fat diet.

Abstract：

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 Delta FosB-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 Delta FosB 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 Delta FosB 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. Delta FosB 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 Delta FosB and dopamine signaling that can be normalized with palatable diets and may be a predisposing phenotype in some forms of obesity.

journal_name

Biol Psychiatry

journal_title

Biological psychiatry

authors

Teegarden SL,Nestler EJ,Bale TL

doi

10.1016/j.biopsych.2008.06.007

subject

Has Abstract

pub_date

2008-12-01 00:00:00

pages

941-50

issue

eissn

0006-3223

issn

1873-2402

pii

S0006-3223(08)00704-X

journal_volume

pub_type

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Delta FosB-mediated alterations in dopamine signaling are normalized by a palatable high-fat diet.