Interleukin-6 and tumor necrosis factor-α attenuate dopamine release in mice fed a high-fat diet, but not medium or low-fat diets.

Chronic low-grade inflammation is associated with a state of diet-induced obesity that impacts systemic tissues and can cross the blood-brain barrier to act directly on the brain. The extent to which pro-inflammatory cytokines released in these conditions affect dopamine presynaptic neurotransmission has not been previously investigated. The purpose of this study was to examine how dopamine terminals are affected by pro-inflammatory cytokines, and to determine if dietary fat consumption potentiates cytokine effects on dopamine release and reuptake rate in the nucleus accumbens (NAc). Male and female C57BL/6J mice were fed high, medium, or low-fat diets (60%, 30%, or 10% total kcals from fat, respectively) for six weeks. Fast scan cyclic voltammetry (FSCV) was used to measure dopamine release and reuptake rate in the NAc core from ex vivo coronal brain slices. Electrically evoked dopamine release and the maximal rate of dopamine reuptake (Vmax) were significantly lower in mice fed the 30% and 60% high-fat diets compared to the 10% low-fat group (p < 0.05). IL-6 5 or 10 nM or TNFα 30 or 300 nM was added to artificial cerebrospinal fluid (aCSF) bathed over brain slices during FSCV. No effect on dopamine release or Vmax was observed with lower concentrations. However, 10 nM IL-6 and 300 nM TNFα significantly reduced dopamine release in the 60% fat group (p < 0.05). No effect of added cytokine was observed on Vmax. Overall, these data provide evidence that dietary fat increases neural responsiveness to cytokines, which may help inform comorbidities between diet-induced obesity and depression or other mood disorders.

Effect of fasting on dopamine neurotransmission in subregions of the nucleus accumbens in male and female mice.

Diets high in saturated fat (HFD) disrupt dopamine neurotransmission, whereas fasting alters tonic and phasic dopamine release to drive motivation and food consumption. However, functional compartments in the nucleus accumbens (NAc) influencing these effects are not well characterized, and sex comparisons have not been made. This study sought to determine whether consumption of a HFD, sex, or being fed versus fasted altered baseline dopamine release and reuptake throughout NAc subregions. Male and female C57BL/6 mice were fed a control diet or nutrient matched HFD for six weeks. Ex-vivo fast-scan cyclic voltammetry revealed females had significantly slower dopamine reuptake in the NAc core than males when fed ad lib control diet. Fasting enhanced dopamine release and reuptake in the NAc core but not the medioventral shell. Further, being fasted versus fed significantly increased dopamine release throughout the NAc core in control males but specifically promoted release and reuptake in only the ventrolateral core of HF-fed males, effects which were lacking in females. Finally, fasting promoted dopamine release and reuptake in the rostral NAc core of controls and more caudally in HFD groups. These data support that dopamine neurotransmission is heterogeneous in NAc subregions and suggest the ventrolateral core is responsive to energy state. Furthermore, a rostrocaudal gradient in the NAc core might control valence responses to fasting that could promote overeating after chronic HFD consumption.