Elsevier

Biological Psychiatry

Volume 64, Issue 11, 1 December 2008, Pages 941-950
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2008.06.007Get rights and content

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.

Section snippets

Animals

Male bitransgenic mice that inducibly overexpress ΔFosB in dynorphin-positive neurons in the NAc and dorsal striatum were generated on a mixed background (ICR:C57Bl6/SJL) at The University of Texas Southwestern Medical Center and maintained and tested at the University of Pennsylvania. All mice were maintained on doxycycline (100 μg/mL in the drinking water) until arrival at the University of Pennsylvania. To induce overexpression, doxycycline was removed (n = 23) (12). Control mice (n = 26)

Basal Biochemical Differences

To elucidate the molecular pathways that underlie the enhanced reward sensitivity in ΔFosB-overexpressing mice, levels of several key signaling molecules were examined in the NAc. There was a trend for increased levels of Cdk5 in the NAc of ΔFosB mice compared with littermate control animals maintained on doxycycline (F = 5.1, p = .08; Figure 1A). ΔFosB mice expressed significantly reduced levels of pCREB (F = 7.4, p < .05; Figure 1B) as well as total levels of CREB (F = 5.4, p = .05; Figure 1

Discussion

In obesity treatment, there is a critical need for identification of factors that influence susceptibility to overeating and weight gain. Brain reward pathways play an important role in the motivation for and response to palatable foods and dietary changes (6, 10, 15, 16). As orexigenic and anorexigenic signals can directly influence reward signaling via a hypothalamus-VTA-NAc circuit, elucidation of genes responsive to energy-rich palatable diets within reward centers may provide novel

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