Increased expression of the Vesicular Glutamate Transporter-1 (VGLUT1) in the prefrontal cortex correlates with differential vulnerability to chronic stress in various mouse strains: effects of fluoxetine and MK-801

Neuropharmacology. 2012 Jan;62(1):503-17. doi: 10.1016/j.neuropharm.2011.09.010. Epub 2011 Sep 17.


Major depression is a chronic psychiatric illness that is highly prevalent and disabling. The available medications are ineffective for many patients suggesting that differents molecular pathways could be specifically altered in the unresponsive patients. Recently, the glutamatergic system has emerged as a target in the research on depression and acute NMDA receptor blockade has been shown to produce strong antidepressant effects. We have studied the adaptations of four mice strains (C57BL/6, DBA/2, C3H and BALB/c) to a chronic unpredictable stress protocol, a widely used model of depression in rodents. BALB/c mice displayed strikingly different behavioral and neurochemical adaptations compared to the other strains tested, suggesting that different molecular pathways are involved in their specific vulnerability. They became hyperactive during the dark period, anhedonic-like and displayed no alterations in the tail suspension test (TST). After chronic stress, only the BALB/c displayed an increased frontocortical VGLUT1 expression which is suggestive of a dysregulation of their prefrontal glutamatergic system, and no BDNF mRNA alteration, although the acute stress modulation of this mRNA is similar to the other strains. Chronic administration of an antagonist of NMDA receptors, MK-801, induced antidepressant-like effects in the TST for stressed BALB/c, but was ineffective for the hyperactivity and anhedonia-like behavior, in contrast to fluoxetine. Chronic MK-801 was totally inactive on the behavior of stressed C57BL/6 mice. MK-801, but not fluoxetine, inhibited the VGLUT1 prefrontal increase in BALB/c. Fluoxetine increased VGLUT1 and BDNF mRNA expression in the hippocampus of the C57BL/6 but not in the BALB/c strain, suggesting a different reactivity in-between strain to both stress and antidepressant. Interestingly enough, the BDNF or VGLUT1 increase is not necessary to reverse the stress induced behavioral alterations in our experimental settings. This observation supports the conclusion that BDNF and VGLUT1 are depressive state markers, but not involved in its etiology. Finally, there is a substantial similarity between the phenotypes that are observed in the BALB/c mice and endogenous depression in humans, as well as between C57BL/6 mice and atypical depression. To have a better understanding of the variability of depression etiologies in human, and the implication of the glutamatergic system, it may be suggested that future animal studies in the mouse would systematically compare the two strains BALB/c and C57BL/6 for the identification of relevant biological mechanisms. This article is part of a special Issue entitled 'Anxiety and Depression'.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Antibodies / pharmacology
  • Antidepressive Agents / pharmacology*
  • Antidepressive Agents / therapeutic use
  • Body Weight / drug effects
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism
  • Disease Models, Animal
  • Dizocilpine Maleate / pharmacology*
  • Dizocilpine Maleate / therapeutic use
  • Fluoxetine / pharmacology*
  • Fluoxetine / therapeutic use
  • Food Preferences / drug effects
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / genetics
  • Hair / drug effects
  • Hair / physiopathology
  • Hindlimb Suspension / psychology
  • Iodine Radioisotopes / pharmacokinetics
  • Male
  • Mice
  • Mice, Inbred Strains
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Prefrontal Cortex / drug effects*
  • RNA, Messenger / metabolism
  • Radioligand Assay
  • Species Specificity
  • Stress, Psychological / drug therapy
  • Stress, Psychological / genetics
  • Stress, Psychological / pathology*
  • Sucrose / administration & dosage
  • Time Factors
  • Vesicular Glutamate Transport Protein 1 / genetics
  • Vesicular Glutamate Transport Protein 1 / metabolism*


  • Antibodies
  • Antidepressive Agents
  • Brain-Derived Neurotrophic Factor
  • Iodine Radioisotopes
  • Neuroprotective Agents
  • RNA, Messenger
  • Vesicular Glutamate Transport Protein 1
  • Fluoxetine
  • Sucrose
  • Dizocilpine Maleate