A High Fat Diet Reduces Dopamine Terminal Function and Increases Behavioral Sensitization to Amphetamine in C57BL/6 Mice

Abstract

High fat (HF) diet-induced obesity has been shown to have a profound impact on neurobiological health, and has been associated with neurodegenerative and addictive disorders involving the mesolimbic dopamine system. Little is known as to how HF alters dopamine neurotransmission, so we used fast scan cyclic voltammetry and behavioral pharmacology to identify dopamine terminal changes that occur in the nucleus accumbens (NAc) of C57BL/6 mice after six-week access to a HF diet. Mice with unrestricted access to HF (60% kcals from fat) gained significantly more weight than chow fed controls (34.5 g and 25.9 g, respectively; p < 0.0001), and exhibited increased behavioral sensitivity to repeated amphetamine (AMPH) administration compared to chow fed mice (p < 0.0001). Baseline evoked dopamine release in the NAc was comparable between chow and HF (0.86 and 1.07 μM, respectively), and baseline Vmax was unaltered by HF (chow: 1.63 μM/s; HF: 1.74 μM/s). A history of AMPH exposure, however, significantly elevated baseline dopamine release in chow (+2.5 fold) but not HF (-0.87 fold) mice (p < 0.001), and HF attenuated baseline reuptake following repeated AMPH (+3.2 vs. +1.3 fold in Vmax for chow and HF, respectively; p < 0.01). HF diet increased the sensitivity of D2 type autoreceptors in the NAc relative to chow; however, HF mice were resistant to enhanced D2 sensitivity that occurred in chow mice after repeated AMPH exposure. These data show that a HF diet reduced the ability of AMPH to change dopamine terminal function. Increased behavioral sensitization to AMPH most likely results from blunted dopamine reuptake in HF mice, and suggests that increased D2 sensitivity is not sufficient to overcome the baseline dopaminergic changes that result from HF.