Molecular mechanisms associated with the antidepressant effects of the class I histone deacetylase inhibitor MS-275 in the rat ventrolateral orbital cortex

Brain Res. 2012 Apr 4;1447:119-25. doi: 10.1016/j.brainres.2012.01.053. Epub 2012 Jan 27.


Histone modifications mediated by histone acetylation are thought to play an important role in the pathogenesis and treatment of depression. Recent studies have revealed that histone deacetylase inhibitors (HDACis), such as sodium valproate (VPA) and MS-275, may be involved in the pathogenesis of depression and in the underpinnings of antidepressant therapeutic action in several brain regions, including the ventrolateral orbital cortex (VLO). In the present study, we investigated whether the class I histone deacetylase inhibitor MS-275 exerts antidepressant-like effects when infused bilaterally into the VLO of a rat, using the forced swimming test (FST) and tail suspension test (TST) as behavioral measures. We found that chronic intra-VLO infusion of MS-275 significantly reduced immobility time in the FST and TST compared with vehicle-treated controls, similar to the effects of systemically administered fluoxetine. These antidepressant-like effects of MS-275 are associated with an increase in H3 acetylation and elevated CREB and BDNF levels in the VLO. Our findings suggest the possibility that alterations in gene expression due to chromatin remodeling, including upregulation of CREB and BDNF, may be involved in the antidepressant-like effect of HDACis in the VLO.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / administration & dosage*
  • Benzamides / administration & dosage*
  • Brain-Derived Neurotrophic Factor / biosynthesis
  • CREB-Binding Protein / biosynthesis
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / enzymology
  • Depression / drug therapy*
  • Depression / enzymology*
  • Histone Deacetylase Inhibitors / administration & dosage*
  • Histone Deacetylases / metabolism*
  • Male
  • Microinjections
  • Pyridines / administration & dosage*
  • Rats
  • Rats, Sprague-Dawley


  • Antidepressive Agents
  • Benzamides
  • Brain-Derived Neurotrophic Factor
  • Histone Deacetylase Inhibitors
  • Pyridines
  • entinostat
  • CREB-Binding Protein
  • Crebbp protein, rat
  • Histone Deacetylases