From Traumatic Childhood to Cocaine Abuse: The Critical Function of the Immune System.

Experiencing traumatic childhood is a risk factor for developing substance use disorder, but the mechanisms that underlie this relationship have not been determined. Adverse childhood experiences affect the immune system, and the immune system mediates the effects of psychostimulants. However, whether this system is involved in the etiology of substance use disorder in individuals who have experienced early life stress is unknown. METHODS: In this study, we performed a series of ex vivo and in vivo experiments in mice and humans to define the function of the immune system in the early life stress-induced susceptibility to the neurobehavioral effects of cocaine. RESULTS: We provide evidence that exposure to social stress at an early age permanently sensitizes the peripheral (splenocytes) and brain (microglia) immune responses to cocaine in mice. In the brain, microglial activation in the ventral tegmental area of social-stress mice was associated with functional alterations in dopaminergic neurotransmission, as measured by whole-cell voltage clamp recordings in dopamine neurons. Notably, preventing immune activation during the social-stress exposure reverted the effects of dopamine in the ventral tegmental area and the cocaine-induced behavioral phenotype to control levels. In humans, cocaine modulated toll-like receptor 4-mediated innate immunity, an effect that was enhanced in those addicted to cocaine who had experienced a difficult childhood. CONCLUSIONS: Collectively, our findings demonstrate that sensitization to cocaine in early life-stressed individuals involves brain and peripheral immune responses and that this mechanism is shared between mice and human