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      Leptin attenuates D 2 receptor‐mediated inhibition of putative ventral tegmental area dopaminergic neurons

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          Abstract

          Obesity causes hyperleptinemia. We have previously shown that D 2 receptor‐mediated inhibition of ventral tegmental area ( VTA) dopaminergic neurons is attenuated in diet‐induced mice with obesity. Consequently, we hypothesized that high concentrations of serum leptin during obesity might modulate D 2 receptor‐mediated effects on VTA dopaminergic neurons. To investigate our hypothesis, we examined leptin effects on D 2 receptor‐mediated inhibition of putative VTA dopaminergic neurons from lean mice using electrophysiological techniques. Leptin (100 nmol/L) directly inhibited spontaneous firing in 71% of putative VTA dopaminergic neurons (leptin‐responsive), whereas the remaining 29% of neurons were leptin‐nonresponsive. In 41% of leptin‐responsive neurons, leptin attenuated the reduced firing rate produced by quinpirole (100 nmol/L), whereas the remaining 59% of neurons exhibited no effect of leptin. In leptin‐nonresponsive neurons, no significant leptin‐induced effect was observed on reduced firing rate produced by quinpirole. In leptin‐responsive neurons with positive leptin‐induced attenuation of quinpirole effects, leptin‐induced attenuation persisted for >20 min, whereas no such persistent attenuation was observed in other types of neurons. In conclusion, leptin attenuates D 2 receptor‐mediated inhibition in a subpopulation of putative VTA dopaminergic neurons. We suggest that leptin directly decreases, and indirectly increases, excitability of VTA dopaminergic neurons. In turn, this may contribute to a change in feeding behavior through the mesolimbic dopaminergic system during the development of obesity.

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          Most cited references27

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          Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system.

          The mesocorticolimbic dopamine system is essential for cognitive and emotive brain functions and is thus an important target in major brain diseases like schizophrenia, drug addiction, and attention deficit hyperactivity disorder. However, the cellular basis for the diversity in behavioral functions and associated dopamine-release pattern within the mesocorticolimbic system has remained unclear. Here, we report the identification of a type of dopaminergic neuron within the mesocorticolimbic dopamine system with unconventional fast-firing properties and small DAT/TH mRNA expression ratios that selectively projects to prefrontal cortex and nucleus accumbens core and medial shell as well as to basolateral amygdala. In contrast, well-described conventional slow-firing dopamine midbrain neurons only project to the lateral shell of the nucleus accumbens and the dorsolateral striatum. Among this dual dopamine midbrain system defined in this study by converging anatomical, electrophysiological, and molecular properties, mesoprefrontal dopaminergic neurons are unique, as only they do not possess functional somatodendritic Girk2-coupled dopamine D2 autoreceptors.
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            Addiction.

            The development of addiction involves a transition from casual to compulsive patterns of drug use. This transition to addiction is accompanied by many drug-induced changes in the brain and associated changes in psychological functions. In this article we present a critical analysis of the major theoretical explanations of how drug-induced alterations in psychological function might cause a transition to addiction. These include: (a) the traditional hedonic view that drug pleasure and subsequent unpleasant withdrawal symptoms are the chief causes of addiction; (b) the view that addiction is due to aberrant learning, especially the development of strong stimulus-response habits; (c) our incentive-sensitization view, which suggests that sensitization of a neural system that attributes incentive salience causes compulsive motivation or "wanting" to take addictive drugs; and (d) the idea that dysfunction of frontal cortical systems, which normally regulate decision making and inhibitory control over behavior, leads to impaired judgment and impulsivity in addicts.
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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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                Author and article information

                Contributors
                s-koyama@daiichi-cps.ac.jp
                Journal
                Physiol Rep
                Physiol Rep
                10.1002/(ISSN)2051-817X
                PHY2
                physreports
                Physiological Reports
                John Wiley and Sons Inc. (Hoboken )
                2051-817X
                02 April 2018
                April 2018
                : 6
                : 7 ( doiID: 10.1002/phy2.2018.6.issue-7 )
                : e13631
                Affiliations
                [ 1 ] Department of Clinical Pharmacology Faculty of Pharmaceutical Sciences Fukuoka University Fukuoka Japan
                [ 2 ] Department of Advanced Pharmacology Daiichi University of Pharmacy Fukuoka Japan
                Author notes
                [*] [* ] Correspondence:

                Susumu Koyama, Department of Advanced Pharmacology, Daiichi University of Pharmacy, 22‐1 Tamagawa‐cho, Minami‐ku, Fukuoka 815‐8511, Japan.

                Tel: +81‐92‐541‐0161

                Fax: +81‐92‐553‐5698

                E‐mail: s-koyama@ 123456daiichi-cps.ac.jp

                Article
                PHY213631
                10.14814/phy2.13631
                5880875
                28cd73b5-fc84-4383-9a4a-b0ed9bed2fd8
                © 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 12 October 2017
                : 30 January 2018
                : 02 February 2018
                Page count
                Figures: 5, Tables: 1, Pages: 10, Words: 5257
                Funding
                Funded by: Japan Society for the Promotion of Science
                Award ID: 22500685
                Award ID: 25350166
                Award ID: 16K00933
                Funded by: Mishima Kaiun Memorial Foundation, Japan
                Award ID: 100176
                Funded by: General Research Institute of Fukuoka University
                Award ID: 106006
                Categories
                Adipose Tissue and Obesity
                Central Nervous System
                Cognitive and Behavioural Neuroscience
                Original Research
                Original Research
                Custom metadata
                2.0
                phy213631
                April 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.4 mode:remove_FC converted:02.04.2018

                brain slice,extracellular recording,receptor interaction

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