Long‐term, calorie‐restricted intake of a high‐fat diet in rats reduces impulse control and ventral striatal D₂ receptor signalling – two markers of addiction vulnerability

Abstract

High impulsivity, mediated through ventral striatal dopamine signalling, represents an established risk factor for substance abuse, and may likewise confer vulnerability to pathological overeating. Mechanistically, the assumption is that trait impulsivity facilitates the initiation of maladaptive eating styles or choices. However, whether consumption of appetitive macronutrients themselves causes deficits in impulse control and striatal signalling, thereby contributing to cognitive changes permissive of overeating behaviour, has yet to be considered. We examined the effects of chronic maintenance on restricted equicaloric, but high-fat or high-sugar, diets (48 kcal/day; 60 kcal% fat or sucrose) on rats' performance in the five-choice serial reaction time task, indexing impulsivity and attention. Markers of dopamine signalling in the dorsal and ventral striatum, and plasma insulin and leptin levels, were also assessed. Rats maintained on the high-fat diet (HFD) were more impulsive, whereas the high-sugar diet (HSD) did not alter task performance. Importantly, body weight and hormone levels were similar between groups when behavioural changes were observed. Maintenance on HFD, but not on HSD, reduced the levels of dopamine D2 receptor (D2 R), cAMP response element-binding protein (CREB) and phosphophorylated CREB (Ser133) proteins in the ventral, but not dorsal, striatum. D2 R expression in the ventral striatum also negatively correlated with impulsive responding, independently of diet. These data indicate that chronic exposure to even limited amounts of high-fat foods may weaken impulse control and alter neural signalling in a manner associated with vulnerability to addictions - findings that have serious implications for the propagation of uncontrolled eating behaviour in obesity and binge-eating disorder.

DRD2: Bridging the Genome and Ingestive Behavior

“…Genetic variants influencing DRD2 signaling therefore affect a significant portion of the population. Finally, there are consistent reports of decreased DRD2 following diet induced obesity [7], high fat diet in the absence of obesity [6], and metabolic dysfunction.…”

“…Consequently, there are many pathways by which genetic variations that impact DA signaling can influence food intake and obesity. In addition, emerging work strongly suggests that adiposity, metabolic dysfunction and diets high in saturated fat and sugar produce adaptations in DA function at the molecular, cellular and circuit levels to impact DA-dependent functions ranging from working memory and compulsive behaviors [6–20] to food preference and nutrient sensing [21, 22] and regulation of glucose metabolism [23–26]. Thus DA genetic variants may influence intake not only by conferring initial risk but also by influencing brain adaptations [27, 28].…”

“…To date no study has directly evaluated the influence of diet on the association between the TaqIA A1 allele and adiposity, metabolic, and/or cognitive dysfunction. However, accumulating evidence from animal studies indicates that diet can influence DA signaling and function independently of body weight, adiposity and metabolic dysfunction [6, 21, 126]. Accordingly, circulating lipids directly modulate DA-mediated food reward [6–11] and obesity-associated cognitive dysfunction is improved by lowering circulating lipids independent of adiposity [127].…”

Basal Ganglia Dysfunction Contributes to Physical Inactivity in Obesity

“…Finally, factors such as sleep duration (Wiers et al, 2016) and caffeine intake (Volkow et al, 2015) can also affect D2R binding, and are not reported or controlled in most clinical studies. These sources of variance can be mitigated in animal studies, which paint a consistent picture of reductions in D2R mRNA (Mathes et al, 2010; Zhang et al, 2015), protein (Adams et al, 2015; Johnson and Kenny, 2010), and receptor binding (Hajnal et al, 2008; Huang et al, 2006; Narayanaswami et al, 2013; van de Giessen et al, 2012; van de Giessen et al, 2013) in obese rodents. Our work extends this body of literature by reporting that other aspects of DA signaling remain unchanged in obese mice, even those with reductions in D2Rs.…”

Mechanisms of Coix Seed Compositions in the Treatment of Spleen Deficiency and Wet Dampness Zheng

“…The genes are closely A B related to water transport, which is the mechanism of SDWD water accumulation. WK Adams also believes that longterm diet disorders cause the body's water and salt metabolism deficiency (Adams et al, 2015). Our previous studies find that the expression of Slc and AQP abnormally in SDWD rats and the expression of Apoa5 and Apoe improves , which indicates that there is abnormal water transport in model rats.…”