Long-term behavioral and neuronal cross-sensitization to amphetamine induced by repeated brief social defeat stress: Fos in the ventral tegmental area and amygdala

Neuroscience. 2004;123(4):857-65. doi: 10.1016/j.neuroscience.2003.10.029.


Repeated exposure to stress induces cross-sensitization to psychostimulants. The present study assessed functional neural activation during social defeat stress-induced sensitization to a subsequent amphetamine challenge. Social defeat stress was induced in intruder rats during short confrontations with an aggressive resident rat once every third day during the course of 10 days. Rats received d-amphetamine injections (1 mg/kg, i.p.) 17 or 70 days after the first social defeat stress exposure. Amphetamine administration induced a significantly higher frequency of locomotor activity in stressed animals than in handled control rats, which was still evident 2 months after the last social stress exposure. Immunohistochemistry for Fos-like proteins was used to detect activated neural profiles in the striatum, nucleus accumbens (NAc), prefrontal cortex, amygdala, and ventral tegmental area (VTA). Repeated social defeat stress significantly increased Fos-like immunoreactive (Fos-LI) labeling 17 days after the start of stress exposure in the prelimbic and infralimbic cortical regions, NAc shell and core, medial, central and basolateral amygdala, and VTA, which probably represented the expression of chronic Fos-related antigens. Amphetamine augmented stress-induced Fos-LI labeling 17 days after the first stress episode in the dorsal striatum, NAc core, and medial amygdala, reflecting a cross-sensitization of Fos response. Amphetamine challenge 70 days after social stress exposures revealed sensitized Fos-LI labeling in the VTA and the amygdala. These data suggest that episodes of repeated social stress induce a long-lasting neural change that leads to an augmented functional activation in the VTA and amygdala, which might represent a neurobiological substrate for long-lasting cross-sensitization of repeated social defeat stress with psychostimulant drugs.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amphetamine / pharmacology*
  • Amygdala / drug effects
  • Amygdala / metabolism*
  • Analysis of Variance
  • Animals
  • Behavior, Animal
  • Cell Count / methods
  • Central Nervous System Stimulants / pharmacology
  • Immunohistochemistry / methods
  • Male
  • Motor Activity / drug effects
  • Proto-Oncogene Proteins c-fos / metabolism*
  • Random Allocation
  • Rats
  • Rats, Long-Evans
  • Social Behavior*
  • Stress, Psychological / metabolism*
  • Time Factors
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism*


  • Central Nervous System Stimulants
  • Proto-Oncogene Proteins c-fos
  • Amphetamine