Epigenetic and pharmacological regulation of 5HT3 receptors controls compulsive ethanol seeking in mice

Factors underlying individual vulnerability to develop alcoholism are largely unknown. In humans, the risk for alcoholism is associated with elevated cue reactivity. Recent evidence suggests that in animal models, reactivity to reward‐paired cues is predictive of addictive behaviors. To model cue reactivity in mice, we used a Pavlovian approach (PA) paradigm in which mice were trained to associate a cue with delivery of a food reinforcer. We then investigated the relationship between PA status with habitual and compulsive‐like ethanol seeking. After training mice to respond for 10% ethanol, habitual behavior was investigated using both an outcome devaluation paradigm, in which ethanol was devalued via association with lithium chloride‐induced malaise, and a contingency degradation paradigm in which the relationship between action and outcome was disrupted. Compulsive‐like behavior was investigated in a modified conditioned place preference paradigm in which footshock was paired with the reward‐paired chamber. PA was found to be predictive of habitual and compulsive‐like ethanol seeking. Additionally, innate risk status was related to epigenetic changes in the gene encoding the requisite subunit of the 5HT3 receptor, Htr3a, as well as 5HT3A protein expression in the amygdala. We then used pharmacological tools to demonstrate that risk status determines the ability of a 5HT3 antagonist to reduce compulsive ethanol seeking. These data indicate that risk status can be identified prior to any alcohol exposure by assessment of cue reactivity, and further that this endophenotype may be predictive of response to pharmacological treatment for components of alcoholism.