Unravelling the Neuroinflammatory Mechanisms Underlying the Effects of Social Defeat Stress on Use of Drugs of Abuse

Abstract

The immune system provides the first line of the organism’s defenses, working to maintain homeostasis against external threats and respond also to internal danger signals. There is much evidence to suggest that modifications of inflammatory parameters are related to vulnerability to develop mental illnesses, such as depression, autism, schizophrenia, and substance use disorders. In addition, not only are inflammatory parameters related to these disorders, but stress also induces the activation of the immune system, as recent preclinical research demonstrates. Social stress activates the immune response in the central nervous system through a number of mechanisms; for example, by promoting microglial stimulation, modifying peripheral and brain cytokine levels, and altering the blood brain barrier, which allows monocytes to traffic into the brain. In this chapter, we will first deal with the most important short- and long-term consequences of social defeat (SD) stress on the neuroinflammatory response. SD experiences (brief episodes of social confrontations during adolescence and adulthood) induce functional modifications in the brain, which are accompanied by an increase in proinflammatory markers. Most importantly, inflammatory mechanisms play a significant role in mediating the process of adaptation in the face of adversity (resilience vs susceptibility), allowing us to understand individual differences in stress responses. Secondly, we will address the role of the immune system in the vulnerability and enhanced sensitivity to drugs of abuse after social stress. We will explore in depth the effects seen in the inflammatory system in response to social stress and how they enhance the rewarding effects of drugs such as alcohol or cocaine. To conclude, we will consider pharmacological and environmental interventions that seek to influence the inflammatory response to social stress and diminish increased drug intake, as well as the translational potential and future directions of this exciting new field of research.