Abstract
The relationship between stress and drug use is well demonstrated. Stress-induced by repeated social defeat (RSD) enhances the conditioned place preference (CPP) induced by cocaine in mice. The phenomenon of resilience understood as the ability of subjects to overcome the negative effects of stress is the focus of increasing interest. Our aim is to characterize the behavior of resilient animals with respect to the effects of RSD on the CPP induced by cocaine. To this end, 25 male C57BL/6 mice were exposed to stress by RSD during late adolescence, while other 15 male mice did not undergo stress (controls). On the 2 days following the last defeat, all the animals carried out the elevated plus maze (EPM) and Hole Board, Social Interaction, Tail Suspension and Splash tests. Three weeks later, all the animals performed the CPP paradigm with a low dose of cocaine (1 mg/kg). Exposure to RSD decreased all measurements related to the open arms of the EPM. It also reduced social interaction, immobility in the tail suspension test (TST) and grooming in the splash test. RSD exposure also increased the sensitivity of the mice to the rewarding effects of cocaine, since only defeated animals acquired CPP. Several behavioral traits were related to resilience to the potentiating effect of RSD on cocaine CPP. Mice that showed less submission during defeat episodes, a lower percentage of time in the open arms of the EPM, low novelty-seeking, high social interaction, greater immobility in the TST and a higher frequency of grooming were those that were resilient to the long-term effects of social defeat on cocaine reward since they behaved like controls and did not develop CPP. These results suggest that the behavioral profile of resilient defeated mice is characterized by an active coping response during episodes of defeat, a greater concern for potential dangers, less reactivity in a situation of inevitable moderate stress and fewer depressive-like symptoms after stress. Determining the neurobehavioral substrates of resilience is the first step towards developing behavioral or pharmacological interventions that increase resilience in individuals at a high risk of suffering from stress.
Highlights
According to the World Health Organization, the global prevalence of cocaine use was estimated at roughly 0.4% of the global population aged 15–64 in 2016, with higher incidence rates in developed societies (World Drug Report, 2018)
Several studies performed in our laboratory using the conditioned place preference (CPP) paradigm have demonstrated that mice exposed to repeated social defeat (RSD) during late adolescence exhibit an enhanced sensitivity to the rewarding effects of low doses of cocaine in adulthood (Montagud-Romero et al, 2016a,b; Rodríguez-Arias et al, 2017; García-Pardo et al, 2019)
RSD increased the rewarding effects of cocaine since only defeated mice spent more time in the drug-paired compartment in Post-C than in Pre-C (p < 0.001)
Summary
According to the World Health Organization, the global prevalence of cocaine use was estimated at roughly 0.4% of the global population aged 15–64 in 2016 (about 18.2 million users), with higher incidence rates in developed societies (World Drug Report, 2018). Among the environmental factors affecting vulnerability to drug addiction, exposure to stress plays a primary role. In preclinical studies with rodents, chronic social stress is modeled by the repeated social defeat (RSD) paradigm. Exposure to RSD has been shown to increase the rewarding effects of drugs of abuse (Ellenbroek et al, 2005; Burke et al, 2011; Aguilar et al, 2013; García-Pardo et al, 2015, 2017; Newman et al, 2018). Several studies performed in our laboratory using the conditioned place preference (CPP) paradigm have demonstrated that mice exposed to RSD during late adolescence exhibit an enhanced sensitivity to the rewarding effects of low doses of cocaine in adulthood (Montagud-Romero et al, 2016a,b; Rodríguez-Arias et al, 2017; García-Pardo et al, 2019)
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