It is well documented that stress-experienced rats evidence an enduring sensitized response to cocaine and facilitation of cocaine self-administration (SA), which were associated to a key involvement of Nucleus Accumbens (NA) core, but not shell. Studies suggest that neuroinflammatory processes may represent a critical issue in stress-induced drug abuse liability. For instance, repeated exposure to stress and addictive drugs may disrupt the microglial phenotype accompanied by structural remodeling. Since the morphometric features of microglia have not yet been described in animal models of chronic stress-induced addictive behaviors, we performed a comparative morphometric analysis of microglia in the NA, core and shell, using a systemic treatment with minocycline, a potent inhibitor of microglia activation. Thus, male rats were restrained 2h daily for a week (day 1-7). From day 16 until completing the experimental protocol, animals received minocycline or vehicle. On day 21, behavioral and immunohistochemical studies were performed. Our results showed that: 1) minocycline prevented chronic stress-induced cocaine sensitization as well as facilitation of cocaine SA, and 2) stress-induced a hyper-ramified microglial profile in the NAcore, but not shell, which was restored by minocycline. These results strongly suggest that NAcore microglia critically contribute to the biological mechanisms underpinning the comorbidity between stress and substance use disorders.