Antidepressants and mood stabilizers effects on histone deacetylase expression in C57BL/6 mice: Brain region specific changes
Introduction
The symptoms of depression can often be improved by agents that increase the synaptic concentrations of monoamines. This finding has led to the adoption of the monoamine hypothesis of depression. However, it does not provide a complete explanation for the actions of antidepressants or for the pathophysiology of depression (Hirschfeld, 2000).
Recently, the superfamily of histone deacetylases (HDACs) has been recognized as an important therapeutic application for a broad range of human disorders, particularly for cancer treatment (Xu et al., 2007; Marsoni et al., 2008; Kim and Bae, 2011) and as a potential treatment for neuropsychiatric disorders (Colvis et al., 2005; Renthal et al., 2007; Tsankova et al., 2007). The role of histone acetylation has emerged as an important post-translational modification that regulates multiple cellular functions including chromatin remodeling and transcriptional regulation (Langley et al., 2005; Bhaumik et al., 2007). Cellular histone acetylation is dynamic and is maintained by two classes of functionally antagonistic enzymes: the histone acetyltransferases (HATs) and the HDACs (Kouzarides, 2007), which are one of the main enzymes involved in chromatin remodeling (Grunstein, 1997; Hsieh and Gage, 2005). It is widely recognized that changes in chromatin structure play a central role in the cognitive impairment associated with psychiatric and neurodegenerative disorders (Abel and Zukin, 2008).
Recent reports have indicated that HDAC5 mRNA expression is associated with treatment efficacy or clinical improvement in the peripheral blood cells of patients undergoing a major depressive episode (Belzeaux et al., 2010; Hobara et al., 2010). Furthermore, hippocampal HDAC5 mRNA is down regulated after chronic treatment with the tricyclic antidepressant imipramine, while viral-mediated HDAC5 overexpression in the hippocampus blocks the effect of imipramine on depression-like behaviors in mice (Tsankova et al., 2006). In addition, sodium butyrate, an HDAC inhibitor, has antidepressant-like effects on behavioral despair in mice (Schroeder et al., 2007).
Thus, targeting histone acetylation may provide benefits for the treatment of depression, schizophrenia, drug addiction, and anxiety disorders (Tsankova et al., 2007). Indeed, sodium valproate, a therapeutic agent for bipolar disorder, is a direct inhibitor of HDACs (Gottlicher et al., 2001; Phiel et al., 2001). These observations together suggest that HDACs are involved in the pathophysiology of mood disorders and the action of antidepressants and mood stabilizers. However, the role of brain region-specific histone modifications in psychiatric drug therapy is still poorly understood.
In this study, we aimed to determine whether mood stabilizers and antidepressants have a similar region-specific effect on tissue monoamine concentrations or protein expression of AcH3 and HDACs. We also attempted to identify which type of HDAC is related to particular antidepressant-like effects in the following regions of the C57BL/6 mouse brain: striatum (ST), nucleus accumbens (Acb), hippocampus (Hip), cingulate cortex (Cg), and amygdala (Amy). Based on the findings, we present the possibility that antidepressant-like effects are associated with changes in HDAC2, HDAC3, or HDAC5 expression in the ST, Cg, or Amy.
Section snippets
Animals
C57BL/6 (wild-type) mice obtained from the Shiga University of Medical Science Laboratory Animal Center (Shiga, Japan) were housed in groups of four or five and maintained on a 12-h light–dark cycle (light phase: 08:00–20:00) in a temperature-controlled environment (22 ± 1 °C) with free access to food and water. All experiments were performed in accordance with the Shiga University of Medical Science guidelines for the care and use of laboratory animals.
Drug treatment
C57BL/6 male mice (8 weeks old) were
Antidepressant- or mood stabilizer-treated mice showed changes in monoamine (dopamine, serotonin, and norepinephrine) concentrations
Subchronic administration of the antidepressants ECM, DLX, and MIR commonly induced significant increases in dopamine and serotonin levels in the ST and Cg, whereas administration of CLM resulted in significant decreases in dopamine, serotonin, and norepinephrine concentrations in the ST and Acb.
Of the mood stabilizers, OLZ and CLZ produced significant increases in dopamine and serotonin levels in the ST. CBZ, LTM, OLZ, and CLZ resulted in significant increases in dopamine and serotonin levels
Discussion
The monoamine hypothesis of depression has previously been implicated in changes to synaptic concentrations. In this study, we showed that the subchronic administration of antidepressants often induced increases in dopamine, serotonin, and norepinephrine in the mouse ST and Cg. Mood stabilizers achieved similar region-specific changes in monoamine content with regard to dopamine, serotonin, and norepinephrine tissue concentrations in the ST, Acb, Hip, and Amy. However, CBZ, LTM, OLZ, and CLZ
Role of funding source
This work was supported by the discretionary expense of the president of the Shiga University of Medical Science.
Contributors
M. Ookubo and H. Kanai designed the research, performed the experiments and co-wrote the manuscript; H. Aoki designed the research; N. Yamada designed the research and co-wrote the manuscript; all authors discussed the results and commented on the manuscript.
Conflict of interest
There are no conflicts of interest including any financial, personal, or other relationships for any of the coauthors related to the work described in the article.
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