Reciprocal changes in prefrontal and limbic dopamine responsiveness to aversive and rewarding stimuli after chronic mild stress: implications for the psychobiology of depression

Biol Psychiatry. 1999 Dec 15;46(12):1624-33. doi: 10.1016/s0006-3223(99)00236-x.


Background: Chronic mild stress (CMS) has been reported to induce behavioral abnormalities that model human depression. To investigate the role in depression of phasic dopamine transmission in cortical and limbic areas, we studied the effect of CMS on the responsiveness of dopamine (DA) transmission to aversive and rewarding stimuli in rats by microdialysis of the nucleus accumbens (NAc) shell and of the medial prefrontal cortex (PFCX).

Methods: Rats were subjected for 30 days to CMS and administered two trials of tail pinch as aversive stimulus and two feeding sessions of a highly palatable food as rewarding stimulus. Concentric microdialysis probes were implanted in the NAc shell and in the medial PFCX.

Results: In unstressed rats, DA decreased in the NAc and increased in the PFCX on the first tail-pinch trial; on the 1st feeding trial, DA increased in the NAc and to a larger extent in the PFCX. In the second tail-pinch trial or feeding trial, these responses were maintained in the PFCX but underwent habituation in the NAc. CMS did not affect basal dialysate DA in the NAc or in the PFCX but influenced the responsiveness of Da transmission to tail pinches and to feeding in a reciprocal manner. Thus, in the tail-pinch trial, CMS reversed the inhibitory response of NAc DA transmission into a stimulatory one and potentiated the stimulatory response in the PFCX. By contrast, in the feeding trial, CMS blunted the stimulatory response of DA transmission in the NAc in the first trial and in the PFCX in the second trial.

Conclusions: CMS reciprocally affected DA responsiveness to motivational stimuli, facilitating or inducing a stimulatory DA response to aversive stimuli but blunting stimulatory responses to rewarding stimuli. Given the postulated role of phasic DA responsiveness in the NAc shell for learning and of DA transmission in the PFCX for expression of motivation, we hypothesize that depression is the result of defective learning and expression of aversive and appetitive motivation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Avoidance Learning
  • Chronic Disease
  • Conditioning, Classical*
  • Depression / metabolism*
  • Dopamine / metabolism*
  • Limbic System / metabolism*
  • Male
  • Microdialysis
  • Nucleus Accumbens / metabolism
  • Prefrontal Cortex / metabolism*
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Reward
  • Stress, Psychological / metabolism*
  • Time Factors


  • Dopamine