Dopaminergic dysregulation in mice selectively bred for excessive exercise or obesity

Abstract

Dysregulation of the dopamine system is linked to various aberrant behaviors, including addiction, compulsive exercise, and hyperphagia leading to obesity. The goal of the present experiments was to determine how dopamine contributes to the expression of opposing phenotypes, excessive exercise and obesity. We hypothesized that similar alterations in dopamine and dopamine-related gene expression may underly obesity and excessive exercise, as competing traits for central reward pathways. Moreover, we hypothesized that selective breeding for high levels of exercise or obesity may have influenced genetic variation controlling these pathways, manifesting as opposing complex traits. Dopamine, dopamine-related peptide concentrations, and gene expression were evaluated in dorsal striatum (DS) and nucleus accumbens (NA) of mice from lines selectively bred for high rates of wheel running (HR) or obesity (M16), and the non-selected ICR strain from which these lines were derived. HPLC analysis showed significantly greater neurotransmitter concentrations in DS and NA of HR mice compared to M16 and ICR. Microarray analysis showed significant gene expression differences between HR and M16 compared to ICR in both brain areas, with changes revealed throughout the dopamine pathway including D1 and D2 receptors, associated G-proteins (e.g., Golf), and adenylate cyclase (e.g., Adcy5). The results suggest that similar modifications within the dopamine system may contribute to the expression of opposite phenotypes in mice, demonstrating that alterations within central reward pathways can contribute to both obesity and excessive exercise.

Figure 1

Wheel running distances (A) and running speed (B) in HR, M16 and ICR mice. Mice were given access to running wheels for 6 days and distances and speeds for days 5 and 6 were averaged. HR mice ran significantly greater distances (F(2,60)=56.82, P<0.001) at greater speeds (F(2,60)=54.37, P<0.001) than M16 and ICR mice. There were no differences in running distance or speed between males and females within the HR or M16 strains. However, within the ICR strain, males ran significantly less than the females (t(17)=3.68, p<0.03). Data are presented as mean +/- SEM.

Figure 2

Peptide concentrations in the nucleus accumbens for ICR, HR and M16 mice. HPLC analysis of tissue samples from nucleus accumbens in HR, M16 and ICR mice was performed to measure tissue concentrations of DA, DOPAC, HVA, NE and 5HIAA. Peptide concentrations for DA (F(2,110)=23.65, p<0.001), DOPAC (F(2,110)=8.14, p<0.01), HVA (F(2,110)=42.65, p<0.001) and NE (F(2,110)=3.44, p<0.05) were significantly higher in HR mice than in M16 or ICR mice. There were no differences in 5HIAA concentrations among the strains. DA concentrations were significantly higher in female compared to male HR mice (F(2,110)=5.26, p<0.01). DA (F(2,110)=5.26, p<0.01), DOPAC (F(2,110)=4.35, p<0.05) and HVA (F(2,110)=7.53, p<0.01) concentrations were significantly higher in male compared to female M16 mice. Data are presented as mean +/- SEM.

Figure 3

Peptide concentrations in the dorsal striatum for ICR, HR and M16 mice. HPLC analysis of tissue samples from dorsal striatum in HR, M16 and ICR mice was performed to measure tissue concentrations of DA, DOPAC, HVA, NE, 5HT and 5HIAA. Peptide concentrations for DA (F(2,92)=60.53, p<0.001), DOPAC (F(2,92)=34.34, p<0.001), HVA (F(2,92)=61.98, p<0.001), 5HT (F(2,92)=6.61, p<0.01) and 5HIAA (F(2,92)=7.37, p<0.01) were significantly higher in HR mice than in M16 or ICR mice. There were no differences in NE concentrations among the strains. 5HIAA concentrations were significantly higher in female compared to male mice across all three strains (F(1,92)=5.40, p<0.05). Female HR mice had lower, while M16 and ICR females had higher, DOPAC concentrations (F(2,92)=4.47, p<0.05) than their male counterparts. Data are presented as mean +/- SEM.