There is increasing evidence to suggest that genetic factors play an important role in the development of alcohol drinking behaviors. It has also been suggested that innate anxiety is an important factor in the initiation of alcohol consumption. Animal lines, such as alcohol-preferring (P) and non-preferring (NP) rats, appear to be suitable models to investigate the neurobiological basis of genetic vulnerability to anxiety and alcohol abuse. The cAMP-responsive element-binding protein (CREB) gene transcription factor and its target gene.neuropeptide Y (NPY), in the central amygdala, have been shown to play a crucial role in anxiety and alcohol abuse. It has been shown that extended amygdaloid circuitries may represent important brain areas as neurobiological substrates that may be involved in anxiety and alcohol drinking behaviors. The mechanisms by which CREB and NPY are regulated ,and also how these signaling molecules in the extended amygdala are involved in anxiety and alcohol drinking behaviors of P rats are unknown. The CREB mediated activation of histone acetyl-transferases (HATs) activity of CREB binding protein (CBP) appears to be an important step in the remodeling of chromatin structure via histone acetylation thereby modulating gene expression. Our proposal is based on the hypothesis that decreased CREB function will alter chromatin remodeling due to decreased acetylation of histones in the extended amygdala, thereby decreasing NPY expression, which in turn could be responsible for the genetic predisposition to anxiety and alcohol-drinking behaviors. The first objective of the proposed study is to examine the role CREB signaling in amygdaloid and bed nucleus of stria terminalis (BNST) structures in relation to anxiety and alcohol drinking behaviors in P and NP rats. The second objective is to investigate the epigenetic mechanisms (histone modifications) by which expression of NPY and NPY-Y1 receptors are altered in the extended amygdala of P rats. A series of genetic and pharmacological manipulations are proposed to study the role of CREB and NPY mechanisms in specific circuitry of extended amygdala of P and NP rats in relation to anxiety-like and alcohol drinking behaviors. Thus, the proposed studies will provide an important clue about the extended amygdala as a neurobiological substrate for the genetic vulnerability toward anxiety and alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA013341-08
Application #
7798559
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Cui, Changhai
Project Start
2001-09-29
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
8
Fiscal Year
2010
Total Cost
$252,599
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
Kyzar, Evan J; Floreani, Christina; Teppen, Tara L et al. (2016) Adolescent Alcohol Exposure: Burden of Epigenetic Reprogramming, Synaptic Remodeling, and Adult Psychopathology. Front Neurosci 10:222
Sakharkar, Amul J; Vetreno, Ryan P; Zhang, Huaibo et al. (2016) A role for histone acetylation mechanisms in adolescent alcohol exposure-induced deficits in hippocampal brain-derived neurotrophic factor expression and neurogenesis markers in adulthood. Brain Struct Funct 221:4691-4703
Pandey, Subhash C (2016) A Critical Role of Brain-Derived Neurotrophic Factor in Alcohol Consumption. Biol Psychiatry 79:427-9
Pandey, Subhash C; Sakharkar, Amul J; Tang, Lei et al. (2015) Potential role of adolescent alcohol exposure-induced amygdaloid histone modifications in anxiety and alcohol intake during adulthood. Neurobiol Dis 82:607-619
Kyzar, Evan J; Pandey, Subhash C (2015) Molecular mechanisms of synaptic remodeling in alcoholism. Neurosci Lett 601:11-9
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
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
Krishnan, Harish R; Sakharkar, Amul J; Teppen, Tara L et al. (2014) The epigenetic landscape of alcoholism. Int Rev Neurobiol 115:75-116
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

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