The multiple faces of footshock punishment in animal research on addiction.

Continued drug use despite negative consequences is a hallmark of addiction commonly modelled in rodents using punished drug intake. Over the years, addiction research highlighted two subpopulations of punishment sensitive and resistant animals. While helpful to interrogate the neurobiology of drug-related behaviors, these procedures carry some weaknesses that need to be recognized and eventually defused. Mainly focusing on footshock-related work, we will first discuss the criteria used to define punishment-resistant animals and how their relative arbitrariness may impact our findings. With the overarching goal of improving our interpretation of the punishment-resistant phenotype, we will evaluate how tailored punishment protocols may better apprehend resistance to punishment, and how testing the robustness of punishment resistance could yield new results and strengthen interpretations. Second, we will question whether and to what extent punishment sensitivity, as currently defined, is reflective of abstinence and suggest that punishment resistance is, in fact, a prerequisite to model abstinence from addiction. Again, we will examine how challenging the robustness of the punishment-sensitive phenotype may help to better characterize it. Finally, we will evaluate whether diminished relapse-like behavior after repeated punishment-induced abstinence could not only contribute to better understand the mechanisms of abstinence, but also uniquely model progressive recovery (i.e., after repeated failed attempts at recovery) which is the norm in people with addiction. Altogether, by questioning the strengths and weaknesses of our models, we would like to open discussions on the different ways we interpret punishment sensitivity and resistance and the aspects that remain to be explored.