Reduced phasic dopamine release and slowed dopamine uptake occur in the nucleus accumbens after a diet high in saturated but not unsaturated fat.

High-fat diets are linked with obesity and changes in dopamine neurotransmission. Mounting evidence shows that saturated fat impacts dopamine neurons and their terminal fields, but little is known about the effect a diet high in unsaturated fat has on the dopamine system. This study sought to determine whether fat type, saturated vs. unsaturated, differentially affected body weight, blood glucose regulation, locomotor behavior, and control of dopamine release and uptake at dopamine neuron terminals in the nucleus accumbens (NAc). C57BL/6 mice were fed a control diet or a nutrient-matched diet high in saturated fat (SF), unsaturated flaxseed oil (Flax) or a blend of the two fats. After 6-weeks, mice from each high-fat diet group gained significantly more weight than Controls, but the group fed Flax gained less weight than the SF group and had fasting blood glucose levels similar to Controls. Ex-vivo fast scan cyclic voltammetry revealed the SF group also had significantly slower synaptic dopamine clearance and a reduced capacity for phasic dopamine release in the nucleus accumbens (NAc), but the Flax and Blend groups resembled Controls. These data show that different types of dietary fat have substantially different effects on metabolic phenotype and influence how dopamine terminals in the NAc regulate dopamine neurotransmission. Our data also suggests that a diet high in unsaturated fat may preserve normal metabolic and behavioral parameters as well as dopamine signaling in the NAc.

The impact of a high-fat diet on physical activity and dopamine neurochemistry in the striatum is sex and strain dependent in C57BL/6J and DBA/2J mice.

BACKGROUND: Obesity has been linked to behavioral and biochemical changes, such as reduced physical activity, dysregulated dopamine metabolism, and gene expression alterations in the brain. The impact of a continuous high-fat diet and resulting state of obesity may vary depending on sex and genetics. OBJECTIVE: The aim of this study was to investigate the impact of a high-fat diet on physical activity, gene expression in the striatum, and dopamine neurochemistry using male and female mice from different strains as a model to examine sex and strain influences on dopamine-mediated behavior and neurobiology. METHODS: Male and female mice from the C57BL/6J (B6J) and DBA/2J (D2J) strains were randomly assigned a control low-fat diet with 10% kcal fat or a high-fat diet with 60% kcal fat for 16 weeks. We assessed ambulation and habituation using the open field test; dopamine release and reuptake using ex-vivo fast scan cyclic voltammetry; and striatal mRNA expression of dopamine receptor D2, alpha synuclein, and tyrosine hydroxylase. RESULTS: Mice fed a high-fat diet exhibited reduced motor activity, but only obese B6J male mice displayed reduced habituation. Dopamine clearance in the dorsal striatum was reduced only in obese D2J mice, while dopamine clearance in the nucleus accumbens core was reduced only in male obese D2J mice. Striatal dopamine receptor D2 gene expression was upregulated exclusively in obese male B6J mice. CONCLUSION: Our study provides evidence for important sex and strain influences on the impact of a high-fat diet and obesity-induced behavior alterations and neurobiology dysregulation in the striatum.

Obesity and dietary fat influence dopamine neurotransmission: exploring the convergence of metabolic state, physiological stress, and inflammation on dopaminergic control of food intake.

The aim of this review is to explore how metabolic changes induced by diets high in saturated fat (HFD) affect nucleus accumbens (NAc) dopamine neurotransmission and food intake, and to explore how stress and inflammation influence this process. Recent evidence linked diet-induced obesity and HFD with reduced dopamine release and reuptake. Altered dopamine neurotransmission could disrupt satiety circuits between NAc dopamine terminals and projections to the hypothalamus. The NAc directs learning and motivated behaviours based on homeostatic needs and psychological states. Therefore, impaired dopaminergic responses to palatable food could contribute to weight gain by disrupting responses to food cues or stress, which impacts type and quantity of food consumed. Specifically, saturated fat promotes neuronal resistance to anorectic hormones and activation of immune cells that release proinflammatory cytokines. Insulin has been shown to regulate dopamine neurotransmission by enhancing satiety, but less is known about effects of diet-induced stress. Therefore, changes to dopamine signalling due to HFD warrant further examination to characterise crosstalk of cytokines with endocrine and neurotransmitter signals. A HFD promotes a proinflammatory environment that may disrupt neuronal endocrine function and dopamine signalling that could be exacerbated by the hypothalamic-pituitary-adrenal and κ-opioid receptor stress systems. Together, these adaptive changes may dysregulate eating by changing NAc dopamine during hedonic versus homeostatic food intake. This could drive palatable food cravings during energy restriction and hinder weight loss. Understanding links between HFD and dopamine neurotransmission will inform treatment strategies for diet-induced obesity and identify molecular candidates for targeted therapeutics.

Kappa Opioid Receptors Negatively Regulate Real Time Spontaneous Dopamine Signals by Reducing Release and Increasing Uptake.

The role of the dynorphin/kappa opioid receptor (KOR) system in dopamine (DA) regulation has been extensively investigated. KOR activation reduces extracellular DA concentrations and increases DA transporter (DAT) activity and trafficking to the membrane. To explore KOR influences on real-time DA fluctuations, we used the photosensor dLight1.2 with fiber photometry in the nucleus accumbens (NAc) core of freely moving male and female C57BL/6 mice. First, we established that the rise and fall of spontaneous DA signals were due to DA release and reuptake, respectively. Then mice were systemically administered the KOR agonist U50,488H (U50), with or without pretreatment with the KOR antagonist aticaprant (ATIC). U50 reduced both the amplitude and width of spontaneous signals in males, but only reduced width in females. Further, the slope of the correlation between amplitude and width was increased in both sexes, suggesting that DA uptake rates were increased. U50 also reduced the frequency of signals in both males and females. All effects of KOR activation were stronger in males. Overall, KORs exerted significant inhibitory control over spontaneous DA signaling, acting through at least three mechanisms - inhibiting DA release, promoting DAT-mediated uptake, and reducing the frequency of signals.

Nicotine modifies cocaine responding in a concurrent self-administration model.

BACKGROUND: Preclinical models of cocaine use disorder (CUD) have not yielded any FDA-approved pharmacotherapies, potentially due to a focus on cocaine use in isolation, which may not fully translate to real-world drug taking patterns. Cocaine and nicotine are commonly used together, and clinical research suggests that nicotine may increase the potency and reinforcing strength of cocaine. In this study, we sought to determine whether and how the addition of nicotine would alter ongoing intravenous cocaine self-administration and motivation to take cocaine in rats. METHODS: Male Sprague-Dawley rats self-administered cocaine alone on a long access, Fixed Ratio one (FR1) schedule, and then switched to a combination of cocaine and nicotine. Finally, rats responded on a Progressive Ratio (PR) schedule for several doses of cocaine alone and in combination with a single dose of nicotine. RESULTS: Under long access conditions, rats co-self-administering cocaine and nicotine responded less and with decreased response rates than for cocaine alone and did not escalate responding. However, under PR conditions that test motivation to take drugs, the dose response curve for the combination was shifted upwards relative to cocaine alone. CONCLUSIONS: Together, these results suggest that nicotine may enhance the reinforcing strength of cocaine, increasing PR responding for cocaine across the dose response curve.

Replacing a Palatable High-Fat Diet with a Low-Fat Alternative Heightens κ-Opioid Receptor Control over Nucleus Accumbens Dopamine.

Diet-induced obesity reduces dopaminergic neurotransmission in the nucleus accumbens (NAc), and stressful weight loss interventions could promote cravings for palatable foods high in fat and sugar that stimulate dopamine. Activation of κ-opioid receptors (KORs) reduces synaptic dopamine, but contribution of KORs to lower dopamine tone after dietary changes is unknown. Therefore, the purpose of this study was to determine the function of KORs in C57BL/6 mice that consumed a 60% high-fat diet (HFD) for six weeks followed by replacement of HFD with a control 10% fat diet for one day or one week. HFD replacement induced voluntary caloric restriction and weight loss. However, fast-scan cyclic voltammetry revealed no differences in baseline dopamine parameters, whereas sex effects were revealed during KOR stimulation. NAc core dopamine release was reduced by KOR agonism after one day of HFD replacement in females but after one week of HFD replacement in males. Further, elevated plus-maze testing revealed no diet effects during HFD replacement on overt anxiety. These results suggest that KORs reduce NAc dopamine tone and increase food-related anxiety during dietary weight loss interventions that could subsequently promote palatable food cravings and inhibit weight loss.