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.
Key Words
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Article info
Publication history
Published online: August 30, 2006
Accepted:
June 28,
2006
Received in revised form:
May 26,
2006
Received:
March 27,
2006
Identification
Copyright
© 2007 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
