Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse.
BACKGROUND
Chromatin remodeling, including changes in histone acetylation, might play a role in the pathophysiology and treatment of depression. We investigated whether the histone deacetylase inhibitor sodium butyrate (SB) administered as single drug or in combination with the selective serotonin reuptake inhibitor (SSRI) fluoxetine exerts antidepressant-like effects in mice.


METHODS
Mice (C57BL/6J) received injections of SB, fluoxetine, or a combination of both drugs either acutely or chronically for a period of 28 days and were subjected to a battery of tests to measure anxiety and behavioral despair. Histone acetylation and expression of brain-derived neurotrophic factor (BDNF) were monitored in hippocampus and frontal cortex.


RESULTS
Co-treatment with SB and fluoxetine resulted in a significant 20%-40% decrease in immobility scores in the tail suspension test (TST), a measure for behavioral despair, both acutely and chronically. In contrast, decreased immobility after single drug regimens was limited either to the acute (fluoxetine) or chronic (SB) paradigm. Systemic injection of SB induced short-lasting histone hyperacetylation in hippocampus and frontal cortex. Among the four treatment paradigms that resulted in improved immobility scores in the TST, three were associated with a transient, at least 50% increase in BDNF transcript in frontal cortex, whereas changes in hippocampus were less consistent.


CONCLUSIONS
The histone deacetylase inhibitor SB exerts antidepressant-like effects in the mouse. The therapeutic benefits and molecular actions of histone modifying drugs, including co-treatment with SSRIs and other newer generation antidepressant medications, warrant further exploration in experimental models.
Schroeder
Frederick A
FA
Brudnick Neuropsychiatric Research Institute, Worcester, Massachusetts, USA.
Lin
Cong Lily
CL
Crusio
Wim E
WE
Akbarian
Schahram
S
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001007:Anxiety / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002087:Butyrates / Q000494:pharmacology*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D046353:Immobility Response, Tonic / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D002087:Butyrates; D004791:Enzyme Inhibitors; D005473:Fluoxetine; D056572:Histone Deacetylase Inhibitors; D017367:Selective Serotonin Reuptake Inhibitors