Repeated exposure of adult rats to transient oxidative stress induces various long-lasting alterations in cognitive and behavioral functions

PLoS One. 2014 Dec 9;9(12):e114024. doi: 10.1371/journal.pone.0114024. eCollection 2014.

Abstract

Exposure of neonates to oxidative stress may increase the risk of psychiatric disorders such as schizophrenia in adulthood. However, the effects of moderate oxidative stress on the adult brain are not completely understood. To address this issue, we systemically administrated 2-cyclohexen-1-one (CHX) to adult rats to transiently reduce glutathione levels. Repeated administration of CHX did not affect the acquisition or motivation of an appetitive instrumental behavior (lever pressing) rewarded by a food outcome under a progressive ratio schedule. In addition, response discrimination and reversal learning were not affected. However, acute CHX administration blunted the sensitivity of the instrumental performance to outcome devaluation, and this effect was prolonged in rats with a history of repeated CHX exposure, representing pro-depression-like phenotypes. On the other hand, repeated CHX administration reduced immobility in forced swimming tests and blunted acute cocaine-induced behaviors, implicating antidepressant-like effects. Multivariate analyses segregated a characteristic group of behavioral variables influenced by repeated CHX administration. Taken together, these findings suggest that repeated administration of CHX to adult rats did not cause a specific mental disorder, but it induced long-term alterations in behavioral and cognitive functions, possibly related to specific neural correlates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal* / drug effects
  • Body Weight / drug effects
  • Cocaine / pharmacology
  • Cognition* / drug effects
  • Cyclohexanones / pharmacology
  • Dopamine / metabolism
  • Dose-Response Relationship, Drug
  • Learning / drug effects
  • Male
  • Oxidative Stress* / drug effects
  • Rats
  • Swimming
  • Time Factors

Substances

  • Cyclohexanones
  • 2-cyclohexen-1-one
  • Cocaine
  • Dopamine

Grants and funding

This study was supported by Grants-in-Aids from the Ministry of Education, Culture, Sports and Technology, Japan (20452097 and 25860994 to YI; 24791208 to SK; 26860920 to HN; 25461727, 25116510, and 26120712 to ST), Eli Lilly (to YI), Japan Foundation for Neuroscience and Mental Health (to YI), Takeda Research Foundation (to ST) and Matsubara Saburoh Memorial Research Foundation for Psychiatry (to SK, ZL and YI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.