The histone deacetylase inhibitor sodium butyrate decreases excessive ethanol intake in dependent animals

Abstract

Converging evidence indicates that epigenetic mechanisms are involved in drug addiction, and that enzymes involved in chromatin remodeling may represent interesting targets in addiction treatment. No study has addressed whether histone deacetylase (HDAC) inhibitors (HDACi) can reduce excessive ethanol intake or prevent relapse in alcohol-dependent animals. Here, we assessed the effects of two HDACi, sodium butyrate (NaB) and MS-275, in the operant ethanol self-administration paradigm in dependent and non-dependent rats. To characterize some of the epigenetic mechanisms associated with alcohol dependence and NaB treatment, we measured the levels of histone H3 acetylation in different brain areas of dependent and non-dependent rats, submitted or not to NaB treatment. Our results demonstrated that (1) NaB and MS-275 strongly decreased excessive alcohol intake of dependent rats in the operant ethanol self-administration paradigm but not of non-dependent rats; (2) NaB reduced excessive drinking and prevented the escalation of ethanol intake in the intermittent access to 20% ethanol paradigm; and (3) NaB completely blocked the increase of ethanol consumption induced by an alcohol deprivation, thus demonstrating a preventive effect of NaB on relapse. The mapping of cerebral histone H3 acetylation revealed a hyperacetylation in the amygdala and cortical areas in dependent rats. Interestingly, NaB did not exacerbate the hyperacetylation observed in these regions, but instead restored it, specifically in cortical areas. Altogether, our results clearly demonstrated the efficacy of NaB in preventing excessive ethanol intake and relapse and support the hypothesis that HDACi may have a potential use in alcohol addiction treatment.

Alcohol Feeding in Mice Promotes Colonic Hyperpermeability and Changes in Colonic Organoid Stem Cell Fate

“…(Palmisano and Pandey, 2017, Kirpich et al, 2013) For example, alcohol craving is associated with brain H3ac deacetylation with a concurrent increase in brain HDAC expression (Palmisano and Pandey, 2017) that can be reversed with administration of oral sodium butyrate. (Simon-O’Brien et al, 2014, Legastelois et al, 2013) Indeed, in the current study H3ac at the Notch1 locus was deacetylated resulting in Notch1 suppression in alcohol-fed mice as shown by ChiP-PCR (Figure 6D). In fact, the Clever’s lab recommends the addition of the HDAC inhibitor valproic acid as a way to activate Notch1 signaling in colonic organoids (Yin et al, 2014) with other studies also demonstrating that HDACi activate Notch1 signaling.…”

Epigenetic mechanisms of alcoholism and stress-related disorders

“…Treatment with TSA was able to attenuate development of anxiety-like behaviors during ethanol withdrawal in rats (Pandey et al, 2008a; You et al, 2014). Interestingly, treatment with HDAC inhibitor, sodium butyrate (NaB) significantly attenuated excessive alcohol intake in dependent rats (Simon-O’Brien et al, 2015). Together, these studies suggest that HDAC inhibitors treatment can restore chromatin remodeling and prevent anxiety-like behaviors and dependent-induced excessive alcohol intake in rats.…”

Histone deacetylase and acetyltransferase inhibitors modulate behavioral responses to social stress

“…Sodium butyrate (NAB; Alfa Aesar, Ward Hill, MA), another HDAC inhibitor, was used in order to further validate that the observed behavioral effects were indeed the result of HDAC inhibition and not another, more rapid effect of VPA administration such as an enhancement in GABAergic signaling. NAB was given IP (600 mg/kg, 1200 mg/kg in physiological saline) to a small subset of animals, but it induced a temporary and extreme ataxia, so systemic use was discontinued, and it was only tested site-specifically (1.32 μg/0.2 μl) (Blank et al, 2014; Heinrichs et al, 2013; Kilgore et al, 2010; Lattal et al, 2007; Mahan et al, 2012; Simon-O'Brien et al, 2015). Finally, Curcumin (Epigentek, Farmingdale, NY, 1.1 μg/0.2 μl) was dissolved in 55% DMSO.…”

“…This drug was chosen because it appears to be one of the few, if not only, HAT inhibitors that is currently commercially available that does not have to be dissolved in 100% DMSO. All site-specific injections were given 30 min before social defeat (Simon-O'Brien et al, 2015; Xing et al, 2011) at a total volume of 0.2 μl to limit the spread of the injection.…”