Neural mechanisms underlying adaptive and maladaptive consequences of stress: Roles of dopaminergic and inflammatory responses

Psychiatry Clin Neurosci. 2019 Nov;73(11):669-675. doi: 10.1111/pcn.12901. Epub 2019 Jul 1.


Stress caused by adverse and demanding conditions, a risk factor for mental illnesses, induces adaptive or maladaptive neural and behavioral consequences, depending on the conditions. Studies using rodent stress models have revealed multiple mechanisms related to dopamine and inflammation for stress-induced neural and behavioral changes. Thus, repeated stress alters activities of ventral tegmental area dopamine neurons projecting to the nucleus accumbens and the medial prefrontal cortex in distinct manners. In the nucleus accumbens, repeated stress decreases activities of D1 receptor-expressing neurons. In the medial prefrontal cortex, single stress increases dopamine D1 receptor signaling, leading to dendritic hypertrophy of excitatory neurons and stress resilience. These changes are attenuated with repetition of stress via prostaglandin E2 , an inflammation-related lipid mediator. Repeated stress activates microglia in the medial prefrontal cortex and the hippocampus. Innate immune receptors, such as the toll-like receptor 2/4 and P2X7, are crucial for repeated stress-induced microglial activation, leading to neural and behavioral changes through proinflammatory cytokines. In addition, repeated stress induces monocyte infiltration to the brain, and impairs the blood-brain barrier in the nucleus accumbens, leading to cytokine leakage to the brain. These monocyte-derived responses are involved in stress-induced behavioral changes. These findings show crucial roles of the accumbal and prefrontal dopamine pathways and inflammatory responses in the brain and body to direct adaptive and maladaptive consequences of stress, and pave the way for identifying a neural origin of stress and understanding the stress-related pathology of mental illnesses.

Keywords: dopamine; microglia; monocyte; prefrontal cortex; stress.

Publication types

  • Review

MeSH terms

  • Adaptation, Psychological*
  • Animals
  • Dopamine*
  • Humans
  • Inflammation / pathology*
  • Receptors, Dopamine
  • Stress, Psychological / pathology*
  • Stress, Psychological / psychology*


  • Receptors, Dopamine
  • Dopamine