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

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.