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

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      Nature neuroscience

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          Abstract

          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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          Most cited references 42

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          Diagnostic and statistical manual of mental disorders.

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            Leptin receptor signaling in midbrain dopamine neurons regulates feeding.

            The leptin hormone is critical for normal food intake and metabolism. While leptin receptor (Lepr) function has been well studied in the hypothalamus, the functional relevance of Lepr expression in the ventral tegmental area (VTA) has not been investigated. The VTA contains dopamine neurons that are important in modulating motivated behavior, addiction, and reward. Here, we show that VTA dopamine neurons express Lepr mRNA and respond to leptin with activation of an intracellular JAK-STAT pathway and a reduction in firing rate. Direct administration of leptin to the VTA caused decreased food intake while long-term RNAi-mediated knockdown of Lepr in the VTA led to increased food intake, locomotor activity, and sensitivity to highly palatable food. These data support a critical role for VTA Lepr in regulating feeding behavior and provide functional evidence for direct action of a peripheral metabolic signal on VTA dopamine neurons.
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              How can drug addiction help us understand obesity?

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                Author and article information

                Journal
                9809671
                21092
                Nat Neurosci
                Nature neuroscience
                1097-6256
                1546-1726
                1 March 2010
                28 March 2010
                May 2010
                1 November 2010
                : 13
                : 5
                : 635-641
                Affiliations
                Laboratory of Behavioral and Molecular Neuroscience, Department of Molecular Therapeutics, The Scripps Research Institute - Scripps Florida, Jupiter, Florida 33458, USA
                Author notes
                [* ]Correspondence to: Paul Kenny, pjkenny@ 123456scripps.edu
                Article
                nihpa181674
                10.1038/nn.2519
                2947358
                20348917

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                Funding
                Funded by: National Institute on Drug Abuse : NIDA
                Award ID: R01 DA025983-02 ||DA
                Categories
                Article

                Neurosciences

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