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      Insulin enhances striatal dopamine release by activating cholinergic interneurons and thereby signals reward

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          Abstract

          Insulin activates insulin receptors (InsRs) in the hypothalamus to signal satiety after a meal. However, the rising incidence of obesity, which results in chronically elevated insulin levels, implies that insulin may also act in brain centres that regulate motivation and reward. We report here that insulin can amplify action potential-dependent dopamine (DA) release in the nucleus accumbens (NAc) and caudate–putamen through an indirect mechanism that involves striatal cholinergic interneurons that express InsRs. Furthermore, two different chronic diet manipulations in rats, food restriction (FR) and an obesogenic (OB) diet, oppositely alter the sensitivity of striatal DA release to insulin, with enhanced responsiveness in FR, but loss of responsiveness in OB. Behavioural studies show that intact insulin levels in the NAc shell are necessary for acquisition of preference for the flavour of a paired glucose solution. Together, these data imply that striatal insulin signalling enhances DA release to influence food choices.

          Abstract

          Insulin signals satiety after a meal; however, the rising incidence of obesity and chronic insulin elevation suggests that insulin may also signal reward. Here, Stouffer et al. show that insulin amplifies dopamine release in rodent striatum depending on diet, and that striatal insulin can influence food choice.

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          Most cited references 64

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          Addiction-like reward dysfunction and compulsive eating in obese rats: Role for dopamine D2 receptors

          We found that development of obesity was coupled with the emergence of a progressively worsening brain reward deficit. Similar changes in reward homeostasis induced by cocaine or heroin is considered a critical trigger in the transition from casual to compulsive drug-taking. Accordingly, we detected compulsive-like feeding behavior in obese but not lean rats, measured as palatable food consumption that was resistant to disruption by an aversive conditioned stimulus. Striatal dopamine D2 receptors (D2R) were downregulated in obese rats, similar to previous reports in human drug addicts. Moreover, lentivirus-mediated knockdown of striatal D2R rapidly accelerated the development of addiction-like reward deficits and the onset of compulsive-like food seeking in rats with extended access to palatable high-fat food. These data demonstrate that overconsumption of palatable food triggers addiction-like neuroadaptive responses in brain reward circuitries and drives the development of compulsive eating. Common hedonic mechanisms may therefore underlie obesity and drug addiction.
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            Brain dopamine and obesity.

            The cerebral mechanisms underlying the behaviours that lead to pathological overeating and obesity are poorly understood. Dopamine, a neurotransmitter that modulates rewarding properties of food, is likely to be involved. To test the hypothesis that obese individuals have abnormalities in brain dopamine activity we measured the availability of dopamine D2 receptors in brain. Brain dopamine D2 receptor availability was measured with positron emission tomography (PET) and [C-11]raclopride (a radioligand for the dopamine D2 receptor). Bmax/Kd (ratio of the distribution volumes in striatum to that in cerebellum minus 1) was used as a measure of dopamine D2 receptor availability. Brain glucose metabolism was also assessed with 2-deoxy-2[18F]fluoro-D-glucose (FDG). Striatal dopamine D2 receptor availability was significantly lower in the ten obese individuals (2.47 [SD 0.36]) than in controls (2.99 [0.41]; p < or = 0.0075). In the obese individuals body mass index (BMI) correlated negatively with the measures of D2 receptors (r=0.84; p < or = 0.002); the individuals with the lowest D2 values had the largest BMI. By contrast, neither whole brain nor striatal metabolism differed between obese individuals and controls, indicating that striatal reductions in D2 receptors were not due to a systematic reduction in radiotracer delivery. The availability of dopamine D2 receptor was decreased in obese individuals in proportion to their BMI. Dopamine modulates motivation and reward circuits and hence dopamine deficiency in obese individuals may perpetuate pathological eating as a means to compensate for decreased activation of these circuits. Strategies aimed at improving dopamine function may be beneficial in the treatment of obese individuals.
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              The neuroscience of natural rewards: relevance to addictive drugs.

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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Pub. Group
                2041-1723
                27 October 2015
                2015
                : 6
                Affiliations
                [1 ]Department of Neuroscience and Physiology, New York University School of Medicine , 550 First Avenue, New York, New York 10016, USA
                [2 ]Department of Neurosurgery, New York University School of Medicine , 550 First Avenue, New York, New York 10016, USA
                [3 ]Center for Neural Science, New York University , 4 Washington Place, New York, New York 10003, USA
                [4 ]Department of Ophthalmology, New York University School of Medicine , 550 First Avenue, New York, New York 10016, USA
                [5 ]Smilow Neuroscience Program, New York University School of Medicine , 550 First Avenue, New York, New York 10016, USA
                [6 ]Department of Psychiatry, New York University School of Medicine , 550 First Avenue, New York, New York 10016, USA
                [7 ]Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine , 550 First Avenue, New York, New York 10016, USA
                Author notes
                [*]

                These authors contributed equally to this work.

                Article
                ncomms9543
                10.1038/ncomms9543
                4624275
                26503322
                Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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