Beneficial effects of benzodiazepine diazepam on chronic stress-induced impairment of hippocampal structural plasticity and depression-like behavior in mice

Behav Brain Res. 2012 Mar 17;228(2):339-50. doi: 10.1016/j.bbr.2011.12.013. Epub 2011 Dec 16.


Whether benzodiazepines (BZDs) have beneficial effects on the progress of chronic stress-induced impairment of hippocampal structural plasticity and major depression is uncertain. The present study designed four preclinical experiments to determine the effects of BZDs using chronic unpredictable stress model. In Experiment 1, several time course studies on behavior and hippocampus response to stress were conducted using the forced swim and tail suspension tests (FST and TST) as well as hippocampal structural plasticity markers. Chronic stress induced depression-like behavior in the FST and TST as well as decreased hippocampal structural plasticity that returned to normal within 3 wk. In Experiment 2, mice received p.o. administration of three diazepam dosages prior to each variate stress session for 4 wk. This treatment significantly antagonized the elevation of stress-induced corticosterone levels. Only low- (0.5mg/kg) and medium-dose (1mg/kg) diazepam blocked the detrimental effects of chronic stress. In Experiment 3, after 7 wk of stress sessions, daily p.o. diazepam administration during 1 wk recovery phase dose-dependently accelerated the recovery of stressed mice. In Experiment 4, 1 wk diazepam administration to control mice enhanced significantly hippocampal structural plasticity and induced an antidepressant-like behavioral effect, whereas 4 wk diazepam administration produced opposite effects. Hence, diazepam can slow the progress of chronic stress-induced detrimental consequences by normalizing glucocorticoid hormones. Considering the adverse effect of long-term diazepam administration on hippocampal plasticity, the preventive effects of diazepam may depend on the proper dose. Short-term diazepam treatment enhances hippocampal structural plasticity and is beneficial to recovery following chronic stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Anti-Anxiety Agents / therapeutic use*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Corticosterone / blood
  • Depression / drug therapy*
  • Depression / etiology
  • Diazepam / therapeutic use*
  • Disease Models, Animal
  • Gene Expression Regulation / drug effects
  • Hindlimb Suspension / psychology
  • Hippocampus / drug effects
  • Hippocampus / pathology*
  • Hippocampus / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuronal Plasticity / drug effects*
  • Neurons / drug effects
  • Stress, Psychological / blood
  • Stress, Psychological / complications
  • Stress, Psychological / pathology*
  • Swimming / psychology
  • Synaptophysin / metabolism
  • Time Factors


  • Anti-Anxiety Agents
  • Brain-Derived Neurotrophic Factor
  • Synaptophysin
  • Diazepam
  • Corticosterone