Anxiety is a common early symptom of ethanol withdrawal and is considered an important factor in the continued use of alcohol by alcoholics. It is also well known that alcohol produces anxiolytic effects. How different epigenetic mechanisms are contributing to changes in neural plasticity associated with alcohol addiction is unknown. Studies have shown the role of changes in chromatin structure due to histone covalent modifications via acetylation and deacetylation in the regulation of gene expression. Histone acetylation is controlled by two groups of enzymes known as histone acetyl-transferases (HATs) and histone deacetylases (HDACs). Three distinct families of HDACs have been described and trichostatin A (ISA) is a potent inhibitor of class I and II HDACs, but not the class III HDACs [silent information regulator 2(Sir2) protein family] which requires a cofactor, nicotinamide-adenine dinucleotide (NAD), for enzymatic activity. It has been shown that phosphorylated cAMP-responsive element binding (p-CREB) regulates neuronal plasticity via recruitment of the HAT associated with CREB binding protein (CBP) to activate gene transcription. Neuropeptide Y (NPY) is one of the CREB-related genes and acts as a potent endogenous anxiolytic compound ,and plays a role in alcoholism. Our proposal is based on the hypothesis that histone modifications, due to an altered acetylation state in the amygdala, are involved in the molecular mechanisms of alcohol dependence. We have proposed several approaches to test this hypothesis specifically by examining a) the effects of acute ethanol on various components of histone acetylation mechanisms as well as NPY expression in the central (CeA), medial (MeA) and basolateral amygdala(BLA) of rats and manipulations of activities of HATs activity and Sir2 in the CeA, MeA, and BLA will also be examined on the anxiolytic properties of ethanol. b) Effects of HDACs inhibitor (Trichostatin A) challenge or intra-amygdaloid Sir 2 inhibitor infusion on anxiety-like behaviors and also on various components of histone acetylation and on NPY expression in amygdala during withdrawal after chronic ethanol exposure. We will also examine the effects of H3 acetylation on NPY mRNA levels in the amygdala during ethanol treatment and its withdrawal. The proposed studies will provide new information on epigenetic mechanisms in the neurocircuitry of the amygdala that may be involved in the process of alcohol dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA016690-04
Application #
7677354
Study Section
Special Emphasis Panel (ZAA1-DD (72))
Program Officer
Reilly, Matthew
Project Start
2006-09-30
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2011-08-31
Support Year
4
Fiscal Year
2009
Total Cost
$205,541
Indirect Cost
Name
University of Illinois at Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Teppen, Tara L; Krishnan, Harish R; Zhang, Huaibo et al. (2016) The Potential Role of Amygdaloid MicroRNA-494 in Alcohol-Induced Anxiolysis. Biol Psychiatry 80:711-719
Sakharkar, Amul J; Tang, Lei; Zhang, Huaibo et al. (2014) Effects of acute ethanol exposure on anxiety measures and epigenetic modifiers in the extended amygdala of adolescent rats. Int J Neuropsychopharmacol 17:2057-67
Sakharkar, Amul J; Zhang, Huaibo; Tang, Lei et al. (2014) Effects of histone deacetylase inhibitors on amygdaloid histone acetylation and neuropeptide Y expression: a role in anxiety-like and alcohol-drinking behaviours. Int J Neuropsychopharmacol 17:1207-20
Krishnan, Harish R; Sakharkar, Amul J; Teppen, Tara L et al. (2014) The epigenetic landscape of alcoholism. Int Rev Neurobiol 115:75-116
You, Chang; Zhang, Huaibo; Sakharkar, Amul J et al. (2014) Reversal of deficits in dendritic spines, BDNF and Arc expression in the amygdala during alcohol dependence by HDAC inhibitor treatment. Int J Neuropsychopharmacol 17:313-22
Zhang, Xiaolu; Kusumo, Handojo; Sakharkar, Amul J et al. (2014) Regulation of DNA methylation by ethanol induces tissue plasminogen activator expression in astrocytes. J Neurochem 128:344-9
Moonat, Sachin; Sakharkar, Amul J; Zhang, Huaibo et al. (2013) Aberrant histone deacetylase2-mediated histone modifications and synaptic plasticity in the amygdala predisposes to anxiety and alcoholism. Biol Psychiatry 73:763-73
Arora, Devinder S; Nimitvilai, Sudarat; Teppen, Tara L et al. (2013) Hyposensitivity to gamma-aminobutyric acid in the ventral tegmental area during alcohol withdrawal: reversal by histone deacetylase inhibitors. Neuropsychopharmacology 38:1674-84
Moonat, Sachin; Pandey, Subhash C (2012) Stress, epigenetics, and alcoholism. Alcohol Res 34:495-505
Sakharkar, Amul J; Zhang, Huaibo; Tang, Lei et al. (2012) Histone deacetylases (HDAC)-induced histone modifications in the amygdala: a role in rapid tolerance to the anxiolytic effects of ethanol. Alcohol Clin Exp Res 36:61-71

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