Aberrant Histone Deacetylase2–Mediated Histone Modifications and Synaptic Plasticity in the Amygdala Predisposes to Anxiety and Alcoholism

Abstract

Background Epigenetic mechanisms have been implicated in psychiatric disorders, including alcohol dependence. However, the epigenetic basis and role of specific histone deacetylase (HDAC) isoforms in the genetic predisposition to anxiety and alcoholism is unknown. Methods We measured amygdaloid HDAC activity, levels of HDAC isoforms and histone H3 acetylation in selectively-bred alcohol-preferring (P) and -nonpreferring (NP) rats. We employed HDAC2 siRNA infusion into the central nucleus of amygdala (CeA) of P rats to determine the causal role of HDAC2 in anxiety-like and alcohol-drinking behaviors. Chromatin immunoprecipitation analysis was performed to examine the histone acetylation status of brain-derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton associated protein (Arc) genes. Golgi-Cox staining was performed to measure dendritic spine density. Results We found that P rats innately display higher nuclear HDAC activity and HDAC2, but not HDAC 1, 3, 4, 5, and 6 protein levels, and lower acetylation of H3-K9, but not H3-K14, in the CeA and medial nucleus of amygdala (MeA) compared with NP rats. Acute ethanol exposure decreased amygdaloid HDAC activity and HDAC2 protein levels, increased global and gene (BDNF and Arc)-specific histone acetylation and attenuated anxiety-like behaviors in P rats, but had no effects in NP rats. HDAC2 knockdown in the CeA attenuated anxiety-like behaviors and voluntary alcohol, but not sucrose, consumption in P rats and increased histone acetylation of BDNF and Arc with a resultant increase in protein levels that correlated with increased dendritic spine density. Conclusions These novel data demonstrate the role of HDAC2-mediated epigenetic mechanisms in anxiety and alcoholism.

Hyposensitivity to Gamma-Aminobutyric Acid in the Ventral Tegmental Area During Alcohol Withdrawal: Reversal by Histone Deacetylase Inhibitors

“…This is further supported by recent findings that TSA treatment during withdrawal after chronic ethanol exposure corrected the deficits in H3-K9 acetylation by blocking the upregulation of HDAC activity in the amygdala and prevented the development of anxietylike behaviors in rats (Pandey et al, 2008). Furthermore, it has been shown that knockdown of HDAC2 in the central nucleus of amygdala attenuated alcohol intake in alcoholpreferring rats (Moonat et al, 2013). The current report is the first of which we are aware demonstrating that in vitro administration of an HDACi can reverse the effects of in vivo ethanol treatment.…”

“…The few studies performed with respect to HDAC-induced histone deacetylation in response to alcohol administration have focused on the forebrain (Pandey et al, 2008;Moonat et al, 2013;Sakharkar et al, 2012). In particular, changes in histone acetylation associated with drug abuse have centered on the amygdala (Pandey et al, 2008;Sakharkar et al, 2012) and the NAc (Renthal and Nestler, 2009b).…”

“…The histone H3 is acetylated at the lysine nine position (H3-K9) by HDAC2, and it is this histone modification that has been associated with gene expression related to drug abuse and neural plasticity (Renthal and Nestler, 2008;Shibasaki et al, 2011). More recently, higher HDAC2 expression-induced deficits in histone H3-K9 acetylation and associated synaptic plasticity in the amygdala has been shown to be involved in alcoholdrinking behaviors (Moonat et al, 2013). However, the role of HDAC-induced histone modification in the reduction of GABA sensitivity in the VTA during alcohol withdrawal has not been examined.…”

Seventy-Five Years of Comorbidity Research

“…Also, Kushner et al (2011) and Kushner et al (2012a) support the hypothesis that the same sensitivity to allostatic dysregulation in the brain's stress and affect response systems (e.g., sympathoadrenal-medullary complex) could render individuals vulnerable to both the development of internalizing disorders and the development of dependence on multiple substances of abuse. Along these same lines, several recent articles fi nd overlapping neurobiological structures and processes underlying a variety of psychiatric disturbances and substance dependence (McElligott et al, 2013;Moonat et al, 2013;Saal et al, 2003). In fact, an entire recent issue of the National Institute on Alcohol Abuse and Alcoholism's journal Alcohol Research: Current Reviews (34[4], 2012) was devoted to the association of neurobiological stress systems to the use of alcohol and development of dependence.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…By using histone deacetylase inhibitors, Sakharkar et al (2012) showed in alcohol-preferring P rats that a rapid tolerance is produced to this anxiolytic effect during chronic ethanol treatment via possible epigenetic changes causing a reduction in NPY expression. It is quite possible that these epigenetic changes are far more frequent and affect the transcription of many genes important for plasticity (Nestler, 2014) and that epigenetic mechanisms can also contribute to genetic vulnerability to increased alcohol consumption, at least in animal models (Moonat et al, 2013).…”