trichostatin-a and Alcoholism

Alcohol use disorder (AUD) represents a serious public health issue, and discovery of new therapies is a pressing necessity. Alcohol exposure has been widely demonstrated to modulate epigenetic mechanisms, such as histone acetylation/deacetylation balance, in part via histone deacetylase (HDAC) inhibition. Epigenetic factors have been suggested to play a key role in AUD. To date, 18 different mammalian HDAC isoforms have been identified, and these have been divided into four classes. Since recent studies have suggested that both epigenetic mechanisms underlying AUD and the efficacy of HDAC inhibitors (HDACIs) in different animal models of AUD may involve class I HDACs, we herein report the development of class I HDACIs, including information regarding their structure, potency, and selectivity. More effort is required to improve the selectivity, pharmacokinetics, and toxicity profiles of HDACIs to achieve a better understanding of their efficacy in reducing addictive behavior.

Topics: Alcoholism; Animals; Epigenomics; Histone Deacetylase Inhibitors; Humans; Therapeutics

Ethanol is a deleterious agent that causes various kinds of neuronal damage to both the developing and adult brain. Recent research on alcoholism implicates impaired function of neural stem cell (NSC) in the pathogenesis of ethanol-induced brain dysfunction. We previously reported that the differentiation of NSCs into neurons was significantly influenced by ethanol. We also found that neuron-restrictive silencer factor/repressor element 1-silencing transcription factor (NRSF/ REST) binding activity potentiated by ethanol underlies the mechanism of ethanol inhibition of neuronal differentiation. Epigenetics refers to post-translational modifications of DNA and nuclear proteins that produce lasting alterations in patterns of gene expression. Epigenetic mechanism plays a critical role of neuronal plasticity and there is clear evidence that dysfunction of epigenetic mechanism also contributes to neurological and psychiatric illness. We will review epigenetic regulation in pathogenesis of psychiatric illness including alcoholism. We also demonstrated that trichostatin A, histone deacetylase inhibitor, reduced the ethanol-induced suppression of neuronal differentiation of NSCs. We suggest that ethanol alters the function of neural differentiation through the mechanism of potentiation of NRSF/REST binding and histone modifications.

Topics: Alcoholism; Animals; Brain Damage, Chronic; Cell Differentiation; DNA; Enzyme Inhibitors; Epigenesis, Genetic; Ethanol; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Neuronal Plasticity; Neurons; Protein Processing, Post-Translational; Repressor Proteins; Stem Cells

Alcohol use disorders are chronic debilitating diseases characterized by severe withdrawal symptoms that contribute to morbidity and relapse. GABA

Topics: Acetylation; Alcoholism; Animals; Cerebral Cortex; Ethanol; Histone Deacetylase 2; Histone Deacetylases; Hydroxamic Acids; Locomotion; Male; Maze Learning; Prefrontal Cortex; Rats; Receptors, GABA-A; Reflex, Righting; Zolpidem

Binge drinking is common during adolescence and can lead to the development of psychiatric disorders, including alcoholism in adulthood. Here, the role and persistent effects of histone modifications during adolescent intermittent ethanol (AIE) exposure in the development of anxiety and alcoholism in adulthood were investigated. Rats received intermittent ethanol exposure during post-natal days 28-41, and anxiety-like behaviors were measured after 1 and 24 h of the last AIE. The effects of AIE on anxiety-like and alcohol-drinking behaviors in adulthood were measured with or without treatment with the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA). Amygdaloid brain regions were collected to measure HDAC activity, global and gene-specific histone H3 acetylation, expression of brain-derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton-associated (Arc) protein and dendritic spine density (DSD). Adolescent rats displayed anxiety-like behaviors after 24 h, but not 1 h, of last AIE with a concomitant increase in nuclear and cytosolic amygdaloid HDAC activity and HDAC2 and HDAC4 levels leading to deficits in histone (H3-K9) acetylation in the central (CeA) and medial (MeA), but not in basolateral nucleus of amygdala (BLA). Interestingly, some of AIE-induced epigenetic changes such as, increased nuclear HDAC activity, HDAC2 expression, and decreased global histone acetylation persisted in adulthood. In addition, AIE decreased BDNF exons I and IV and Arc promoter specific histone H3 acetylation that was associated with decreased BDNF, Arc expression and DSD in the CeA and MeA during adulthood. AIE also induced anxiety-like behaviors and enhanced ethanol intake in adulthood, which was attenuated by TSA treatment via normalization of deficits in histone H3 acetylation of BDNF and Arc genes. These novel results indicate that AIE induces long-lasting effects on histone modifications and deficits in synaptic events in the amygdala, which are associated with anxiety-like and alcohol drinking behaviors in adulthood.

Topics: Acetylation; Alcoholism; Animals; Anxiety Disorders; Binge Drinking; Brain; Brain-Derived Neurotrophic Factor; Central Nervous System Depressants; Cytoskeletal Proteins; Disease Models, Animal; Ethanol; Gene Expression; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Histones; Hydroxamic Acids; Male; Nerve Tissue Proteins; Rats, Sprague-Dawley; Underage Drinking

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.

Topics: Alcoholism; Animals; Behavior, Animal; Brain; Central Nervous System Depressants; Chromatin Assembly and Disassembly; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Enzyme Inhibitors; Ethanol; Exploratory Behavior; Gene Expression; Histone Acetyltransferases; Histone Deacetylases; Hydroxamic Acids; Male; Maze Learning; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome