Characterization and enhancement of resilience to the effects of social stress on the rewarding properties of cocaine in male mice

Resumen

The main focus of the present PhD Thesis was to study resilience to the development of a cocaine use disorder after exposure to stress. For this purpose, we used animal models of social stress (intermittent repeated social defeat, IRSD) and drug reward (paradigm of conditioned place preference, CPP), since we have previously seen that exposure to IRSD increases the rewarding effects of cocaine in the CPP paradigm in mice (García-Pardo et al., 2019; Calpe-López et al., 2020). Our aim was to identify animals that are resilient to the long-term potentiation of cocaine CPP induced by IRSD, to characterize the behavioral profile of such mice and to identify environmental manipulations that enhance their resilience. To characterize the profile of resilient mice several behavioral tests were performed shortly after IRSD, including the Elevated Plus Maze, Hole-Board, Social Interaction, Splash and Tail Suspension Tests. In the first study we observed that exposure to IRSD in late adolescence induced negative consequences, such as anxiety- and depressionlike symptoms (social interaction deficits and anhedonia), and an increased sensitivity to cocaine reward; however, mice that displayed an active coping strategy during defeat (low submission) were resilient to most of these effects. In the second and third studies we demonstrated that voluntary physical exercise during adolescence and a brief period of maternal separation at an early age enhanced resilience to the effects of IRSD in adulthood. In the fourth study, to assess the stress inoculation hypothesis, we demonstrated that a slight stressor in early adolescence, such as a brief period of immobilization, visualization of social defeat of another animal, or acute social defeat, protected against the negative consequences of subsequent exposure to IRSD. In our last study, we explored the implication of age as a variable of resilience. In mice exposed to IRSD in early adolescence, low submission was associated with resilience to the depression-like effects and potentiation of cocaine CPP induced by IRSD. From a translational point of view, our research may help the design of new preventive interventions and more effective treatments for substance use and other stress-related disorders, allowing individuals to cope with social stress in a more effective way. Characterization of the individual variables that confer resilience and identification of pro-resilience strategies, such as physical exercise, are critical for the development of behavioral, pharmacological and environmental therapies that can promote resilience in more vulnerable subjects.