Intermittent voluntary wheel running promotes resilience to the negative consequences of repeated social defeat in mice.

A novel approach to reduce the incidence of substance use disorders is to promote resilience to stress using environmental resources such as physical exercise. In the present study we test the hypothesis that Voluntary Wheel Running (VWR) during adolescence blocks the negative consequences of stress induced by intermittent repeated social defeat (IRSD). Four groups of adolescent male C57BL/6 mice were employed in the experiment; two groups were exposed to VWR (1 h, 3 days/week) from postnatal day (PND) 21 until the first social defeat (PND 47), while the remaining two groups did not have access to activity wheels (controls). On PND 47, 50, 53 and 56 mice, who had performed VWR, were exposed to an episode of social defeat by a resident aggressive mouse (VWR+IRSD group) or allowed to explore an empty cage (VWR+EXPL group). The same procedure was performed with control mice that had not undergone VWR (CONTROL+IRSD and CONTROL+EXPL groups). On PND 57, all the mice performed the Elevated Plus Maze (EPM), Hole-Board, Social Interaction, Tail Suspension and Splash tests. After an interval of 3 weeks, all mice underwent a conditioned place preference (CPP) procedure with 1 mg/kg of cocaine. Exposure to VWR prevented the negative consequences of social stress in the EPM, splash test and CPP, since the VWR+IRSD group did not display anxiety- or depression-like effects or the potentiation of cocaine reward observed in the Control+IRSD group. Our results support the idea that physical exercise promotes resilience to stress and represents an excellent target in drug abuse prevention.

Brief Maternal Separation Inoculates Against the Effects of Social Stress on Depression-Like Behavior and Cocaine Reward in Mice.

Exposure to intermittent repeated social defeat (IRSD) increases the vulnerability of mice to the rewarding effects of cocaine in the conditioned place preference (CPP) paradigm. According to the "inoculation of stress" hypothesis, a brief period of maternal separation (MS) can provide protection against the negative effects of IRSD. The aim of the present study was to assess whether exposure to a brief episode of MS prevents the subsequent short-term effects of IRSD on depression- and anxiety-like behaviors and to explore its long-term effects on cocaine CPP in mice. Four groups of male C57BL/6 mice were employed; two groups were separated from their mother [6 h on postnatal day (PND) 9], while the other two groups were not (controls). On PND 47, 50, 53 and 56, mice that had experienced MS were exposed to social defeat in the cage of an aggressive resident mouse (MS + IRSD group) or were allowed to explore an empty cage (MS + EXPL group). The same procedure was performed with control mice that had not experienced MS (CONTROL + IRSD and CONTROL + EXPL groups). On PND57-58, all the mice performed the elevated plus maze and the hole-board, social interaction and splash tests. Three weeks after the last episode of defeat, all the mice underwent the CPP procedure with cocaine (1 mg/kg). Irrespective of whether or not MS had taken place, a reduction in open arms measures, dips, and social interaction was observed in mice that experienced IRSD. A higher latency of grooming and acquisition of cocaine-induced CPP were observed only in mice exposed to IRSD alone (CONTROL + IRSD). These results suggest that exposure to a brief episode of stress early in life increases the subsequent resilience of animals to the effects of social stress on vulnerability to cocaine.