Epigenetic and Proteomic Expression Changes Promoted by Eating Addictive-like Behavior (2015)

Neuropsychopharmacology. 2015 May 6. doi: 10.1038/npp.2015.129.

Mancino S1, Burokas A1, Gutiérrez-Cuesta J1, Gutiérrez-Martos M1, Martín-García E1, Pucci M2, Falconi A2, D’Addario C3, Maccarrone M4, Maldonado R1.


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 CB1 gene promoter was revealed in the prefrontal cortex of addict-like mice, which was associated to an up-regulation of CB1 protein expression in the same brain area. The pharmacological blockade (rimonabant 3 mg/Kg; ip) 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 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.