Brain chromatin remodeling: a novel mechanism of alcoholism - PubMed (original) (raw)

Brain chromatin remodeling: a novel mechanism of alcoholism

Subhash C Pandey et al. J Neurosci. 2008.

Abstract

The treatment of alcoholism requires the proper management of ethanol withdrawal symptoms, such as anxiety, to prevent further alcohol use and abuse. In this study, we investigated the potential role of brain chromatin remodeling, caused by histone modifications, in alcoholism. We found that the anxiolytic effects produced by acute alcohol were associated with a decrease in histone deacetylase (HDAC) activity and increases in acetylation of histones (H3 and H4), levels of CREB (cAMP-responsive element binding) binding protein (CBP), and neuropeptide Y (NPY) expression in the amygdaloid brain regions of rats. However, the anxiety-like behaviors during withdrawal after chronic alcohol exposure were associated with an increase in HDAC activity and decreases in acetylation of H3 and H4, and levels of both CBP and NPY in the amygdala. Blocking the observed increase in HDAC activity during alcohol withdrawal with the HDAC inhibitor, trichostatin A, rescued the deficits in H3 and H4 acetylation and NPY expression (mRNA and protein levels) in the amygdala (central and medial nucleus of amygdala) and prevented the development of alcohol withdrawal-related anxiety in rats as measured by the elevated plus maze and light/dark box exploration tests. These results reveal a novel role for amygdaloid chromatin remodeling in the process of alcohol addiction and further suggest that HDAC inhibitors may be potential therapeutic agents in treating alcohol withdrawal symptoms.

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Figures

Figure 1.

Figure 1.

A, B, The effect of acute ethanol exposure (1 h after 1 g/kg; i.p.) on open-arm and closed-arm activity in the EPM test (A) and on LDB exploration test (B) for anxiety-like behaviors. Values are the mean ± SEM of 11–12 rats in each group. *Significantly different from n-saline-treated rats (p < 0.01–0.001).

Figure 2.

Figure 2.

A, Acute ethanol exposure inhibited HDAC activity in the amygdala of rats [injected with ethanol (1 h after 1 g/kg, i.p.) or n-saline]. The HDAC activity was determined in the cell lysates of amygdala by measuring the deacetylation of acetylated lysine side chains. The values are the mean ± SEM of seven rats per group. *Significantly different from n-saline-treated rats (p < 0.01; Student's t test). B, Low-magnification photomicrographs of acetylated histones H3 (Lys 9) and H4 (Lys 8) and CBP gold-immunolabeling (protein levels) in central amygdaloid (CeA) structures of n-saline or acute-ethanol-treated rats. Scale bar, 40 μm. C, Effect of acute ethanol treatment on protein levels of acetylated H3 and H4, and of CBP in various amygdaloid (CeA, MeA, and BLA) structures of rats. Values are the mean ± SEM of seven to nine rats per group. *Significantly different from the n-saline-treated rats (p < 0.001; Student's t test).

Figure 3.

Figure 3.

A, Low-magnification photomicrographs of NPY mRNA (in situ RT-PCR) and NPY gold-immunolabeling (protein) in CeA of n-saline and acute ethanol-treated rats. Scale bar, 40 μm. B, Effect of acute ethanol treatment on mRNA and protein levels of NPY in CeA, MeA, and BLA of rats. Values are the mean ± SEM of five rats per group. *Significantly different from the n-saline-treated rats (p < 0.001; Student's t test).

Figure 4.

Figure 4.

A, Effect of TSA treatment on open-arm and closed-arm activities in the EPM test for anxiety-like behaviors during ethanol withdrawal. The control diet-fed, ethanol diet-fed (0 h withdrawal), and ethanol diet-fed (24 h withdrawal) rats were injected with TSA (2 mg/kg, i.p.) or vehicle once, 2 h before measuring anxiety-like behaviors. The groups are represented as follows: control diet-fed + vehicle = control + vehicle; control diet-fed + TSA = control + TSA; ethanol diet-fed (0 h withdrawal) + vehicle = ethanol + vehicle; ethanol diet-fed (24 h withdrawal) + vehicle = withdrawal + vehicle; ethanol diet-fed (24 h withdrawal) + TSA = withdrawal + TSA. Values are the mean ± SEM of eight to nine rats per group. *Significantly different from control diet-fed rats treated with vehicle (p < 0.001; ANOVA followed by Tukey's test). B, Effect of TSA treatment on LDB exploration test for anxiety-like behaviors during ethanol withdrawal after chronic ethanol exposure. Values are the mean ± SEM of nine rats per group. *Significantly different from control diet-fed rats treated with vehicle (p < 0.01–0.001; ANOVA followed by Tukey's test).

Figure 5.

Figure 5.

A, Effect of ethanol withdrawal after chronic ethanol treatment and effect of TSA treatment on HDAC activity in the amygdala of rats. The HDAC activity was determined in the cell lysates of amygdala by measuring the deacetylation of acetylated lysine side chains. Values are the mean ± SEM of seven rats per group. *Significantly different from control diet-fed rats treated with vehicle (p < 0.05; ANOVA followed by Tukey's test). B, Low-magnification photomicrographs of acetylated histones H3 (Lys 9) and H4 (Lys 8), and CBP gold-immunolabeling (protein levels) in the CeA of control diet-fed, ethanol-fed, and ethanol-withdrawn rats treated with TSA or vehicle. Scale bar, 40 μm. The groups are represented as follows: control diet-fed + vehicle = control + vehicle; control diet-fed + TSA = control + TSA; ethanol diet-fed (0 h withdrawal) + vehicle = ethanol + vehicle; ethanol diet-fed (24 h withdrawal) + vehicle = withdrawal + vehicle; ethanol diet-fed (24 h withdrawal) + TSA = withdrawal + TSA. C, Effect of TSA treatment on protein levels of acetylated H3 and H4, and CBP in the CeA, MeA, and BLA of rats during ethanol withdrawal after chronic ethanol exposure. Values are the mean ± SEM of five to six rats per group. *Significantly different from the control diet-fed rats treated with vehicle (p < 0.001; ANOVA followed by Tukey's test).

Figure 6.

Figure 6.

A, Low-magnification photomicrographs of NPY mRNA and NPY gold-immunolabeling (protein) in the CeA of control diet-fed, ethanol diet-fed, and ethanol-withdrawn rats treated with TSA or vehicle. Scale bar, 40 μm. The groups are represented as follows: control diet-fed + vehicle = control + vehicle; control diet-fed + TSA = control + TSA; ethanol diet-fed (0 h withdrawal) + vehicle = ethanol + vehicle; ethanol diet-fed (24 h withdrawal) + vehicle = withdrawal + vehicle; ethanol diet-fed (24 h withdrawal) + TSA = withdrawal + TSA. B, Effect of TSA treatment on protein and mRNA levels of NPY in the CeA, MeA, and BLA of rats during ethanol withdrawal after chronic ethanol exposure. Values are the mean ± SEM of five to six rats per group. *Significantly different from the control diet-fed rats treated with vehicle (p < 0.001; ANOVA followed by Tukey's test).

Figure 7.

Figure 7.

Proposed model for chromatin remodeling in the central and medial nucleus of amygdala during acute and chronic ethanol exposure. The present investigation reveals that increased histone acetylation caused by either inhibition of HDACs or activation of HATs (increased CBP levels) may lead to increased expression of NPY in the amygdala that may be operative in the anxiolytic effects of acute ethanol exposure in rats. However, ethanol withdrawal-related anxiety might be related to decreased histone acetylation caused by activation of HDACs or inhibition of HATs (decreased CBP levels), and may also be responsible for the observed decrease in NPY expression in the amygdala. TSA treatment during ethanol withdrawal attenuated anxiety-like behaviors and rescued the reductions in both histone acetylation and NPY expression in the CeA and MeA during ethanol withdrawal. Thus, HDAC-induced chromatin remodeling in the amygdala may be crucial in the dynamic process that occurs during the development of alcoholism.

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