Abstract
Background
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 humans.
Keywords
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Article info
Publication history
Published online: June 11, 2018
Accepted:
May 29,
2018
Received in revised form:
May 28,
2018
Received:
November 29,
2017
Identification
Copyright
© 2018 Society of Biological Psychiatry.
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- Activation of the Immune System During a Developmental Window May Provide a Link Between Early Life Stress and Future Susceptibility to Cocaine AbuseBiological PsychiatryVol. 84Issue 12
- PreviewA greater appreciation of the integrative relationship between the immune system and central nervous system is emerging in light of evidence suggesting that bidirectional communication can promote both neuropsychiatric health and disease. Substance use disorder and stress-related disorders (e.g., depression) are associated with an increased expression of inflammatory markers in the periphery and brain parenchyma (1,2). Research indicates that stress and many drugs of abuse each independently alters peripheral immune and brain-resident microglia function (2,3).
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