Pavlovian conditioning and cross-sensitization studies raise challenges to the hypothesis that overeating is an addictive behavior.

Elevated glucocorticoid levels and sign tracking (ST) in Pavlovian conditioning are potential biomarkers of compulsive behaviors such as addiction. As overeating is sometimes viewed as a form of addictive behavior, we hypothesized that murine Pavlovian sign trackers would have a greater propensity to overeat and develop obesity. Using a food reward in the classical conditioning paradigm, we show that ST behavior is a robust conditioned response but not a predictor of eating and growth trajectories in mice, thus challenging the view that the development of obesity and drug addiction depend on identical mechanisms. This interpretation was supported by experiments which showed that overweight mice do not display cross-sensitization to an addictive drug (morphine), and conversely, that overweight morphine-sensitized animals do not overconsume a highly rewarding food. Although the rewarding/motivational effects of both food and drugs of abuse are mediated by similar neurochemical mechanisms, obesity and drug addiction represent a summation of other dysfunctional input and output pathways that lead to the emergence of two distinct disorders, each of which would deserve a specific pharmacotherapeutic approach.