High fat diet augments amphetamine sensitization in mice: Role of feeding pattern, obesity, and dopamine terminal changes

Abstract

High fat (HF) diet-induced obesity has been shown to augment behavioral responses to psychostimulants that target the dopamine system. The purpose of this study was to characterize dopamine terminal changes induced by a HF diet that correspond with enhanced locomotor sensitization to amphetamine. C57BL/6J mice had limited (2hr 3d/week) or extended (24h 7d/week) access to a HF diet or standard chow for six weeks. Mice were then repeatedly exposed to amphetamine (AMPH), and their locomotor responses to an amphetamine challenge were measured. Fast scan cyclic voltammetry was used to identify changes in dopamine terminal function after AMPH exposure. Exposure to a HF diet reduced dopamine uptake and increased locomotor responses to acute, high-dose AMPH administration compared to chow fed mice. Microdialysis showed elevated extracellular dopamine in the nucleus accumbens (NAc) coincided with enhanced locomotion after acute AMPH in HF-fed mice. All mice exhibited locomotor sensitization to amphetamine, but both extended and limited access to a HF diet augmented this response. Neither HF-fed group showed the robust amphetamine sensitization-induced increases in dopamine release, reuptake, and amphetamine potency observed in chow fed animals. However, the potency of amphetamine as an uptake inhibitor was significantly elevated after sensitization in mice with extended (but not limited) access to HF. Conversely, after amphetamine sensitization, mice with limited (but not extended) access to HF displayed reduced autoreceptor sensitivity to the D2/D3 agonist quinpirole. Additionally, we observed reduced membrane dopamine transporter (DAT) levels after HF, and a shift in DAT localization to the cytosol was detected with limited access to HF. This study showed that different patterns of HF exposure produced distinct dopamine terminal adaptations to repeated AMPH, which differed from chow fed mice, and enhanced sensitization to AMPH. Locomotor sensitization in chow fed mice coincided with elevated DAT function and increased AMPH potency; however, the enhanced behavioral response to AMPH after HF exposure was unique in that it coincided with reduced DAT function and diet pattern-specific adaptations.

High-Fat-Diet-Induced Deficits in Dopamine Terminal Function Are Reversed by Restoring Insulin Signaling

“…32 Mice with access to high fat gained ~2.5 times more weight than control-chow-fed littermates over the 6 weeks, replicating the weight gain observed in previous studies, which resulted in hyper-insulinemia, 33 hyperleptinemia, 34 and elevated serum triglycerides. 31 Significant differences in body weight were detected as early as 3 weeks ( p < 0.01), with final averaged body weights of 24.88 ± 1.16 and 31.36 ± 3.06 g for control and high-fat-fed mice, respectively ( p < 0.001) (Figure 1B). Two-way analysis of variance (ANOVA) detected main effects of time ( F 18,324 = 127.36, p < 0.0001) and diet ( F 1,324 = 15.33, p = 0.001) with a time × diet interaction ( F 18,324 = 27.09, p < 0.0001).…”

“…High fat-fed mice have an increased ratio of cytosolic to membrane DAT, but greater overall DAT in tissue lysate from the NAc. 31 Improving insulin signaling in high fat insulin-resistant mice putatively supports redistribution of the DAT to the plasma membrane where a functional increase in DAT activity can be measured with voltammetry. To rule out the possibility that high-fat mice simply had reduced insulin receptor content in the NAc, we used a quantitative ELISA to measure total insulin receptor protein in the NAc ( n = 7, controls; n = 8, high fat).…”

Impact of Early Consumption of High-Fat Diet on the Mesolimbic Dopaminergic System

“…Interestingly, sucrose consumption during adolescence leads to long-lasting deficits of reward processing (Frazier et al, 2008; Vendruscolo et al, 2010; Naneix et al, 2016) and HFD consumption in adolescent but not adult rats increases locomotor sensitivity to psychostimulants (Baladi et al, 2015; Fordahl et al, 2016), suggesting a particular impact of high-energy diet consumed during adolescence on the DA system (Reichelt, 2016). …”

Short post‐weaning social isolation induces long‐term changes in the dopaminergic system and increases susceptibility to psychostimulants in female rats

“…Here we have two facts: (1) The chronic exposure to HSD was not able to sensitize the dopaminergic system. It is possible that a different temporal pattern of availability would have a distinct outcome on the diet effects concerning the dopaminergic system (Fordahl et al, 2016). Accordingly, studies using intermittent access to high palatable food showed greater AMPH‐locomotor response than those using a chronic availability (Avena et al, 2012; Fordahl et al, 2016).…”