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Downregulation of nucleus accumbens D1 and D2 receptor expression occurs upon exposure to and persists long-term after withdrawal from palatable food: conclusions from diet-induced obesity models
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
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(English)Manuscript (preprint) (Other academic)
Identifiers
URN: urn:nbn:se:uu:diva-119449OAI: oai:DiVA.org:uu-119449DiVA: diva2:300941
Note
The nucleus accumbens (NAcc) mediates feeding reward; its activity reflects tastants’ hedonic value. The NAcc dopamine guides immediate responses to reward, however, its involvement in establishing long-term responses after a period of exposure to palatable foods has not been defined. Furthermore, reward-driven overeating propels weight increase, but the scale of weight gain depends on animals’ obesity-prone (OP) or -resistant (OR) phenotype. It is unclear whether responses of NAcc dopamine to palatable foods depend on susceptibility to obesity. We investigated the effect of restricted and unrestricted extended access to high-fat high-sugar (HFHS) diet on expression of genes encoding dopamine receptors in the NAcc of OP and OR rats. We examined persistence of HFHS diet-induced changes in D1 and D2 gene expression in OP and OR rats subjected to HFHS withdrawal by receiving bland chow for 18 days after HFHS. Effects of restricted access to HFHS by pair-feeding to bland chow-fed controls were also studied. Using RT-PCR, we found that NAcc D1 mRNA was downregulated after long-term HFHS access in OP vs. OR animals. The effect persisted after 18 days of HFHS withdrawal. Noteworthy, even restricted HFHS led to downregulation of D1 as well as of D2 mRNA levels compared to chow-fed controls. Detection of concurrent expression changes of mu and kappa opioid receptors in the NAcc and caudate putamen confirmed their link to the effects of feeding reward withdrawal. We conclude that exposure to palatability has lasting consequences for the NAcc dopamine system, perhaps underlying the persistent search for feeding reward. The fact that the NAcc D1 expression changes long-term in OP animals after both un- and restricted exposure to palatability and extends well into the reward discontinuation phase, implicates the D1 receptor with the propensity to overeat and, in effect, gain weight in obesity prone individuals.Available from: 2010-03-01 Created: 2010-02-25 Last updated: 2010-03-01
In thesis
1. From Food Preference to Craving: Behavioural Traits and Molecular Mechanisms
Open this publication in new window or tab >>From Food Preference to Craving: Behavioural Traits and Molecular Mechanisms
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Preference for palatable and energy-dense foods may be a risk factor for body weight gain and has both genetic and environmental components. Once obesity develops in an individual, weight loss is difficult to achieve. Indeed, obesity is often characterized by repeated attempts to reduce the overconsumption of energy-dense foods, followed by food craving and relapse to overconsumption. Relapse and loss of control over intake are observed also in drug addicts, and it has been shown that obesity and drug addiction not only share behavioural features but also neural circuitry, e.g. the mesolimbic dopamine pathway. In this thesis, we sought to investigate the mechanisms related to food preferences and craving using animal models previously used in addiction research.

The risk of gaining weight may implicate behavioural traits and emotional states. We showed in rats that a risk-taking behavioural profile was associated both with increased preference for a high-fat (HF) diet and with increased motivational response to a palatable high-sucrose (HS) diet. Hypothalamic urocortin 2 expression was associated with the preference for the HF diet. We also tested the hypothesis that consumption of HS and HF diets separately or provided simultaneously (HFHS) affect anxiety-like behaviour and locomotion.

Furthermore, we showed that withdrawal from HFHS food affects diet-induced obesity-prone (OP) and obesity-resistant (OR) animals differently. OP animals had increased motivation (craving) for HS food pellets as measured by the operant self-administration technique during withdrawal. Dopamine receptor expression in the striatum differed between OP and OR animals both at access to HFHS and during withdrawal. This strongly implicates dopaminergic signaling in the OP phenotype.

In humans, food preferences may be monitored using questionnaires. We analyzed food preference data from parents of preschool children, and identified an inverse association of parental preference for high-fat high-protein food and overweight in children.

In conclusion, we have employed animal models previously used in the addiction field to identify molecular mechanisms related both to food preference and vulnerability to obesity, and to food craving associated with withdrawal from palatable food. These findings add to our current understanding of obesity.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 93 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 526
Keyword
Obesity, Reward, Food preferences, Dietary fats, Dietary carbohydrates, Anxiety, Dopamine, Craving, Operant self-administration
National Category
Pharmacology and Toxicology
Research subject
Pharmacology
Identifiers
urn:nbn:se:uu:diva-119779 (URN)978-91-554-7734-9 (ISBN)
Public defence
2010-04-10, B42, BMC, Husargatan 3, Uppsala, 09:00 (English)
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Available from: 2010-03-19 Created: 2010-03-01 Last updated: 2010-03-19Bibliographically approved

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