title: Epigenetic and Proteomic Expression Changes Promoted by Eating Addictive-Like Behavior.
abstract: An increasing perspective conceptualizes obesity and overeating as disorders related to addictive-like processes that could share common neurobiological mechanisms. In the present study, we aimed at validating an animal model of eating addictive-like behavior in mice, based on the DSM-5 substance use disorder criteria, using operant conditioning maintained by highly palatable chocolate-flavored pellets. For this purpose, we evaluated persistence of food-seeking during a period of non-availability of food, motivation for food, and perseverance of responding when the reward was associated with a punishment. This model has allowed identifying extreme subpopulations of mice related to addictive-like behavior. We investigated in these subpopulations the epigenetic and proteomic changes. A significant decrease in DNA methylation of CNR1 gene promoter was revealed in the prefrontal cortex of addict-like mice, which was associated with an upregulation of CB1 protein expression in the same brain area. The pharmacological blockade (rimonabant 3 mg/kg; i.p.) of CB1 receptor during the late training period reduced the percentage of mice that accomplished addiction criteria, which is in agreement with the reduced performance of CB1 knockout mice in this operant training. Proteomic studies have identified proteins differentially expressed in mice vulnerable or not to addictive-like behavior in the hippocampus, striatum, and prefrontal cortex. These changes included proteins involved in impulsivity-like behavior, synaptic plasticity, and cannabinoid signaling modulation, such as alpha-synuclein, phosphatase 1-alpha, doublecortin-like kinase 2, and diacylglycerol kinase zeta, and were validated by immunoblotting. This model provides an excellent tool to investigate the neurobiological substrate underlying the vulnerability to develop eating addictive-like behavior.
authors.affiliation: Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Samantha
authors.initials: S
authors.lastname: Mancino
authors.affiliation: Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Aurelijus
authors.initials: A
authors.lastname: Burokas
authors.affiliation: Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Gutiérrez-Cuesta
authors.affiliation: Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Gutiérrez-Martos
authors.affiliation: Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Martín-García
authors.affiliation: Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Pucci
authors.affiliation: Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Falconi
authors.affiliation: Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.|Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Addario
authors.affiliation: Center of Integrated Research, Campus Bio-Medico University of Rome, and European Center for Brain Research/Santa Lucia Foundation, Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
authors.affiliation: Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000235:genetics / Q000378:metabolism*; D001835:Body Weight / Q000235:genetics; D001921:Brain / Q000378:metabolism*; D003216:Conditioning, Operant / Q000502:physiology; D019852:Diacylglycerol Kinase / Q000378:metabolism; D000089742:Doublecortin-Like Kinases; D044127:Epigenesis, Genetic / Q000502:physiology*; D057890:Epigenomics; D005247:Feeding Behavior / Q000502:physiology; D006963:Hyperphagia / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D040901:Proteomics; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency / Q000235:genetics*; D012054:Reinforcement, Psychology; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D043884:Receptor, Cannabinoid, CB1; D051844:alpha-Synuclein; D019852:Diacylglycerol Kinase; C512480:diacylglycerol kinase zeta, mouse; D000089742:Doublecortin-Like Kinases; C485525:Dclk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D010744:Phosphoric Monoester Hydrolases