Using the social defeat (SD) model, numerous studies have shown that stressed mice display an enhanced response to the motivational effects of cocaine in the self-administration (SA) and conditioned-place preference (CPP) paradigms. However, not all subjects exposed to stress express its harmful effects. Some are particularly susceptible to the deleterious effects of repeated SD, while resilient mice successfully cope with stressful experiences and display adjusted psychological functioning after stress. Vulnerability to develop stress-related disorders, such as depression, has been linked to coping strategies and more recently to individual differences in the immune system. However, no studies have evaluated if coping strategies and immune system reactivity to social stress experiences can also predict susceptibility to stress-induced enhancement of the cocaine response. We evaluated cocaine response in socially defeated mice in the CPP and SA paradigms. To evaluate neuroimmune reactivity to stress the pro-inflammatory cytokine IL-6 and the chemokine CX3CL1 were measured in the striatum and hippocampus. Behavioral phenotype during and after SD episodes was also evaluated. Our results showed that susceptible mice to the depressive-like behaviors effects of stress showed increased conditioned rewarding effects of cocaine in the CPP. In addition, susceptible mice displayed passive-reactive coping behavior during social stress episodes and more pronounced changes in neuroinflammatory markers after the last SD episode, which lasted for one month. Although the complex mechanisms underlying susceptibility or resilience to social stress are still unclear, our results point to multiple adaptive stress responses expressed at different phenotypic levels.