Frustrated expected reward induces differential transcriptional changes in the mouse brain

Addict Biol. 2015 Jan;20(1):22-37. doi: 10.1111/adb.12188. Epub 2014 Oct 6.


Frustration represents a particular aspect of the addictive process that is related to loss of control when the expected reward is not obtained. We aim to study the consequences of frustrated expected reward on gene expression in the mouse brain. For this purpose, we used an operant model of frustration using palatable food as reward combined with microarrays. Transcriptomic profiles of frontal cortex, ventral striatum and hippocampus were analysed in five groups of mice: (1) positive control receiving palatable food and the cue light as conditioned stimulus; (2) frustrated group only receiving the cue light; (3) extinction learning group that did not receive palatable food nor the light; (4) negative control that never received the reinforcer nor the light during the whole experiment; and (5) yoked that received palatable food passively. Gene expression changes produced by frustration were revealed in the frontal cortex and ventral striatum, but not in the hippocampus. Most of the changes, such as the modification of the dopamine-DARPP-32 signalling pathway, were common in both areas and estimated to have neuronal origin. Extinction learning induced transcriptional changes only in the ventral striatum, with most genes showing down-regulation and without alteration in the dopamine-DARPP-32 signalling pathway. Active palatable food-seeking behaviour induced changes in gene expression in ventral striatum mainly affecting cell communication. In conclusion, frustration behaviour-induced changes in frontal cortex and ventral striatum mainly related to dopamine-DARPP-32 signalling that could play an important role in the loss of behavioural control during the addictive processes.

Keywords: DARPP-32; frustration; gene expression; operant behaviour; palatable food; progressive ratio; transcriptomics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism*
  • Conditioning, Operant / physiology*
  • Dopamine and cAMP-Regulated Phosphoprotein 32 / genetics
  • Food
  • Frontal Lobe / metabolism
  • Frustration*
  • Gene Expression
  • Gene Expression Profiling
  • Hippocampus / metabolism
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins / genetics
  • Male
  • Mice
  • RNA, Messenger / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Reward*
  • SOXD Transcription Factors / genetics
  • Sex-Determining Region Y Protein / genetics
  • Signal Transduction
  • Trans-Activators / genetics
  • Transcription Factors / genetics
  • Transcriptome*
  • Ventral Striatum / metabolism


  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins
  • Nkx2-5 protein, mouse
  • Ppp1r1b protein, mouse
  • RNA, Messenger
  • SOXD Transcription Factors
  • Sex-Determining Region Y Protein
  • Sox5 protein, mouse
  • Sry protein, mouse
  • Trans-Activators
  • Transcription Factors
  • pancreatic and duodenal homeobox 1 protein