Epigenetic and proteomic expression changes promoted by eating addictive-like behavior

Samantha Mancino, Aurelijus Burokas, Javier Gutiérrez-Cuesta, Miriam Gutiérrez-Martos, Elena Martín-García, Mariangela Pucci, Anastasia Falconi, Claudio D'Addario, Mauro Maccarrone, Rafael Maldonado

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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 CB 1 protein expression in the same brain area. The pharmacological blockade (rimonabant 3 mg/kg; i.p.) of CB 1 receptor during the late training period reduced the percentage of mice that accomplished addiction criteria, which is in agreement with the reduced performance of CB 1 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.

Original languageEnglish
Pages (from-to)2788-2800
Number of pages13
Issue number12
Publication statusPublished - May 6 2015


ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Mancino, S., Burokas, A., Gutiérrez-Cuesta, J., Gutiérrez-Martos, M., Martín-García, E., Pucci, M., Falconi, A., D'Addario, C., Maccarrone, M., & Maldonado, R. (2015). Epigenetic and proteomic expression changes promoted by eating addictive-like behavior. Neuropsychopharmacology, 40(12), 2788-2800. https://doi.org/10.1038/npp.2015.129