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.
Key Words
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Article info
Publication history
Published online: July 28, 2008
Accepted:
June 7,
2008
Received in revised form:
June 6,
2008
Received:
January 15,
2008
Identification
Copyright
© 2008 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
