Chromatin remodeling — a novel strategy to control excessive alcohol drinking

Harmful excessive use of alcohol has a severe impact on society and it remains one of the major causes of morbidity and mortality in the population. However, mechanisms that underlie excessive alcohol consumption are still poorly understood, and thus available medications for alcohol use disorders are limited. Here, we report that changing the level of chromatin condensation by affecting DNA methylation or histone acetylation limits excessive alcohol drinking and seeking behaviors in rodents. Specifically, we show that decreasing DNA methylation by inhibiting the activity of DNA methyltransferase (DNMT) with systemic administration of the FDA-approved drug, 5-azacitidine (5-AzaC) prevents excessive alcohol use in mice. Similarly, we find that increasing histone acetylation via systemic treatment with several histone deacetylase (HDAC) inhibitors reduces mice binge-like alcohol drinking. We further report that systemic administration of the FDA-approved HDAC inhibitor, SAHA, inhibits the motivation of rats to seek alcohol. Importantly, the actions of both DNMT and HDAC inhibitors are specific for alcohol, as no changes in saccharin or sucrose intake were observed. In line with these behavioral findings, we demonstrate that excessive alcohol drinking increases DNMT1 levels and reduces histone H4 acetylation in the nucleus accumbens (NAc) of rodents. Together, our findings illustrate that DNA methylation and histone acetylation control the level of excessive alcohol drinking and seeking behaviors in preclinical rodent models. Our study therefore highlights the possibility that DNMT and HDAC inhibitors can be used to treat harmful alcohol abuse

Chromatin remodeling--a novel strategy to control excessive alcohol drinking.

Harmful excessive use of alcohol has a severe impact on society and it remains one of the major causes of morbidity and mortality in the population. However, mechanisms that underlie excessive alcohol consumption are still poorly understood, and thus available medications for alcohol use disorders are limited. Here, we report that changing the level of chromatin condensation by affecting DNA methylation or histone acetylation limits excessive alcohol drinking and seeking behaviors in rodents. Specifically, we show that decreasing DNA methylation by inhibiting the activity of DNA methyltransferase (DNMT) with systemic administration of the FDA-approved drug, 5-azacitidine (5-AzaC) prevents excessive alcohol use in mice. Similarly, we find that increasing histone acetylation via systemic treatment with several histone deacetylase (HDAC) inhibitors reduces mice binge-like alcohol drinking. We further report that systemic administration of the FDA-approved HDAC inhibitor, SAHA, inhibits the motivation of rats to seek alcohol. Importantly, the actions of both DNMT and HDAC inhibitors are specific for alcohol, as no changes in saccharin or sucrose intake were observed. In line with these behavioral findings, we demonstrate that excessive alcohol drinking increases DNMT1 levels and reduces histone H4 acetylation in the nucleus accumbens (NAc) of rodents. Together, our findings illustrate that DNA methylation and histone acetylation control the level of excessive alcohol drinking and seeking behaviors in preclinical rodent models. Our study therefore highlights the possibility that DNMT and HDAC inhibitors can be used to treat harmful alcohol abuse

Erratum: MicroRNA-30a-5p in the prefrontal cortex controls the transition from moderate to excessive alcohol consumption

MicroRNAs (miRNAs) induce messenger RNA (mRNA) degradation and repress mRNA translation. Several miRNAs control the expression of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex (PFC). The BDNF signaling pathway is activated by moderate intake of alcohol to prevent escalation to excessive drinking. Here, we present data to suggest that the transition from moderate to uncontrolled alcohol intake occurs, in part, upon a breakdown of this endogenous protective pathway via a miRNA-dependent mechanism. Specifically, a mouse paradigm that mimics binge alcohol drinking in humans produced a robust reduction in BDNF mRNA levels in the medial PFC (mPFC), which was associated with increased expression of several miRNAs including miR-30a-5p. We show that miR-30a-5p binds the 3' untranslated region of BDNF, and that overexpression of miR-30a-5p in the mPFC decreased BDNF expression. Importantly, overexpression of miR-30a-5p in the mPFC produced an escalation of alcohol intake and a preference over water. Conversely, inhibition of miR-30a-5p in the mPFC using a Locked Nucleic Acid sequence that targets miR-30a-5p restored BDNF levels and decreased excessive alcohol intake. Together, our results indicate that miR-30a-5p plays a key role in the transition from moderate to excessive alcohol intake

MicroRNA-30a-5p in the prefrontal cortex controls the transition from moderate to excessive alcohol consumption.

MicroRNAs (miRNAs) induce messenger RNA (mRNA) degradation and repress mRNA translation. Several miRNAs control the expression of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex (PFC). The BDNF signaling pathway is activated by moderate intake of alcohol to prevent escalation to excessive drinking. Here, we present data to suggest that the transition from moderate to uncontrolled alcohol intake occurs, in part, upon a breakdown of this endogenous protective pathway via a miRNA-dependent mechanism. Specifically, a mouse paradigm that mimics binge alcohol drinking in humans produced a robust reduction in BDNF mRNA levels in the medial PFC (mPFC), which was associated with increased expression of several miRNAs including miR-30a-5p. We show that miR-30a-5p binds the 3′ untranslated region of BDNF, and that overexpression of miR-30a-5p in the mPFC decreased BDNF expression. Importantly, overexpression of miR-30a-5p in the mPFC produced an escalation of alcohol intake and a preference over water. Conversely, inhibition of miR-30a-5p in the mPFC using a Locked Nucleic Acid sequence that targets miR-30a-5p restored BDNF levels and decreased excessive alcohol intake. Together, our results indicate that miR-30a-5p plays a key role in the transition from moderate to excessive alcohol intake

Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2

Epigenetic processes have been implicated in the pathophysiology of alcohol dependence, but the specific molecular mechanisms mediating dependence-induced neuroadaptations remain largely unknown. Here, we found that a history of alcohol dependence persistently decreased the expression of Prdm2, a histone methyltransferase that monomethylates histone 3 at the lysine 9 residue (H3K9me1), in the rat dorsomedial prefrontal cortex (dmPFC). Downregulation of Prdm2 was associated with decreased H3K9me1, supporting that changes in Prdm2 mRNA levels affected its activity. Chromatin immunoprecipitation followed by massively parallel DNA sequencing showed that genes involved in synaptic communication are epigenetically regulated by H3K9me1 in dependent rats. In non-dependent rats, viral-vector-mediated knockdown of Prdm2 in the dmPFC resulted in expression changes similar to those observed following a history of alcohol dependence. Prdm2 knockdown resulted in increased alcohol self-administration, increased aversion-resistant alcohol intake and enhanced stress-induced relapse to alcohol seeking, a phenocopy of postdependent rats. Collectively, these results identify a novel epigenetic mechanism that contributes to the development of alcohol-seeking behavior following a history of dependence.Funding Agencies|NIAAA division of Intramural Research; Swedish Research Council; NIAAA R01 [1R01AA023781-01A1]; United States Department of Defense (DoD), through the National Defense Science and Engineering Graduate Fellowship (NDSEG) Program; US National Institute of Health [DA035592, MH084880, NS071674]; DoD; Army Research Office (ARO); National Defense Science and Engineering Graduate (NDSEG) Fellowship [32 CFR 168a]</p