Brief exposure to predator odor and resultant anxiety enhances mesocorticolimbic activity and enkephalin expression in CD-1 mice

Eur J Neurosci. 2004 Nov;20(9):2415-29. doi: 10.1111/j.1460-9568.2004.03704.x.


The present study assessed alterations in mesolimbic enkephalin (ENK) mRNA levels after predator [2,5-dihydro-2,4,5-trimethylethiazoline (TMT)] and non-predator (butyric acid) odor encounter and/or light-dark (LD) testing in CD-1 mice immediately, 24, 48 and 168 h after the initial odor encounter and/or LD testing. The nucleus accumbens, ventral tegmental area, basolateral (BLA), central (CEA) and medial amygdaloid nuclei, prelimbic and infralimbic cortex were assessed for fos-related antigen (FRA) and/or ENK mRNA as well as neuronal activation of ENK neurons (FRA/ENK). Mice exposed to TMT displayed enhanced freezing and spent less time in the light of the immediate LD test relative to saline- or butyric acid-treated mice. Among mice exposed to TMT, LD anxiety-like behavior was associated with increased FRA in the prelimbic cortex and accumbal shell and decreased ENK-positive neurons in the accumbal core. Mice displaying high TMT-induced LD anxiety exhibited increased ENK-positive neurons in the BLA, CEA and medial amygdaloid nuclei relative to mice that displayed low anxiety-like behavior in the LD test after TMT exposure. In the BLA and CEA, 'high-anxiety' mice also displayed increased FRA/ENK after TMT exposure and LD testing. In contrast to neural cell counts, the level of ENK transcript was decreased in the BLA and CEA of 'high-anxiety' mice after TMT exposure and LD testing. These data suggest that increased FRA may regulate stressor-responsive genes and mediate long-term behavioral changes. Indeed, increased ENK availability in mesolimbic sites may promote behavioral responses that detract from the aversiveness of the stressor experience.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Amygdala / anatomy & histology
  • Amygdala / metabolism
  • Animals
  • Anxiety / chemically induced
  • Anxiety / metabolism
  • Anxiety / physiopathology*
  • Behavior, Animal / physiology
  • Cerebral Cortex / anatomy & histology
  • Cerebral Cortex / metabolism
  • Enkephalins / genetics*
  • Fear / physiology*
  • Limbic System / anatomy & histology
  • Limbic System / drug effects
  • Limbic System / metabolism*
  • Male
  • Mice
  • Neural Pathways / anatomy & histology
  • Neural Pathways / metabolism
  • Neurons / metabolism
  • Nucleus Accumbens / anatomy & histology
  • Nucleus Accumbens / metabolism
  • Odorants
  • Proto-Oncogene Proteins c-fos / genetics
  • RNA, Messenger / metabolism
  • Smell / physiology*
  • Stress, Psychological / genetics
  • Stress, Psychological / metabolism
  • Thiazoles / administration & dosage
  • Up-Regulation / genetics*
  • Ventral Tegmental Area / anatomy & histology
  • Ventral Tegmental Area / metabolism


  • 2,5-dihydro-2,4,5-trimethylthiazoline
  • Enkephalins
  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Thiazoles