Elsevier

Biological Psychiatry

Volume 62, Issue 1, 1 July 2007, Pages 55-64
Biological Psychiatry

Original Article
Antidepressant-Like Effects of the Histone Deacetylase Inhibitor, Sodium Butyrate, in the Mouse

https://doi.org/10.1016/j.biopsych.2006.06.036Get rights and content

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.

Section snippets

Animals

All experiments were conducted with adult male and female C57BL/6J inbred mice (age 9–22 weeks). Animals were housed in groups of 2–4/cage with food and water ad libitum. Animals were purchased directly from the Jackson Laboratory (Bar Harbor, Maine), housed under 12-hour light/dark cycle, and allowed to acclimate to new housing for at least 5–7 days before experimental manipulation. All experimental procedures were approved by the Institutional Animal Care and Use Committee of the University

Systemic Administration of Sodium Butyrate Induces a Transient Increase in Histone Acetylation in Brain and Liver

Butyrate inhibits the activity of most HDAC forms, except class II HDAC 6 and HDAC10 and all class III HDACs (Davie 2003). Previous studies showed that peripheral administration of SB upregulates overall levels of histone acetylation in brain chromatin, but dose-response and temporal course of this effect remain unclear (Dong et al 2005, Ferrante et al 2003). Therefore, we injected mice with 1.2 g/kg SB, a dose that ameliorates the neurological phenotype in a mouse model for Huntington’s

Discussion

We report that in mice, the HDACi SB improves performance in a behavioral despair paradigm, the TST. Notably, combined treatment with SB and the SSRI fluoxetine was superior to fluoxetine monotherapy both in the acute and chronic paradigm. In addition, mice that received SB as a single drug via daily injections over a period of 3 weeks showed a significant improvement in the TST, when applied within a battery of four tests designed to measure behavioral correlates of anxiety and despair. In

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