Signaling Mechanisms in Alcohol Drinking Behaviors

Summary

Principal Investigator: Subhash C Pandey
Abstract: DESCRIPTION (provided by applicant): A variety of factors, including genetic traits, may mediate the development of alcohol-drinking behaviors. Evidence also indicates that negative reinforcing factors, such as high anxiety levels, may play an important role in alcohol use and abuse. However, the epigenetic and signaling mechanisms that may be involved in the comorbidity of anxiety and alcoholism remain unclear. Animal lines, such as selectively bred alcohol-preferring (P) and non-preferring (NP) rats, appear to be suitable models to study the molecular basis of the genetic predisposition to anxiety and alcoholism. Our laboratory recently demonstrated that brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeleton-associated protein (Arc) expression, and dendritic spine density (DSD) were lower in the central (CeA) and medial nucleus of amygdala (MeA) but not basolateral amygdala (BLA) of P rats as compared with NP rats. Despite correlational evidence, it is unknown if decreased BDNF signaling in the amygdaloid circuitry of P rats is responsible for heightened anxiety-like and excessive alcohol- drinking behaviors. It is also unknown how the expression of Arc and various exons of BDNF and its receptor, tyrosine kinase B (trkB)-linked signaling [cAMP responsive-element binding protein (CREB) and extracellular regulated protein kinases 1/2 (Erk1/2)] are regulated and if BDNF signaling modulates synaptic plasticity in the amygdala resulting in the phenotypes of anxiety and alcohol-drinking behaviors of P rats compared with NP rats. One epigenetic regulatory mechanism which has been shown to play a role in the regulation of gene expression is DNA methylation. DNA methyltransferases (DNMT) catalyze DNA methylation allowing for the binding of methyl-CpG-binding proteins and recruitment of several transcriptional suppressors to DNA, thereby decreasing gene transcription. Several genes, such as BDNF, trkB, and Arc, involved in synaptic plasticity are epigenetically controlled by DNA methylation. The association between DNMTs, synaptic plasticity-associated gene expression, and DSD in the amygdala of P and NP rats and its role in anxiety and alcohol-drinking behaviors are currently unknown. The proposal is based on the hypothesis that innately higher DNMT levels will produce DNA hypermethylation-mediated decreases in the expression of BDNF, trkB and Arc leading to decreased DSD in the amygdala and deficits in the BDNF system that may be operative in the predisposition to anxiety and alcoholism. Two novel approaches have been proposed to test the above hypothesis. One approach proposes to investigate DNA methylation mechanisms in the amygdaloid brain circuitry (CeA and MeA) by determining DNMT (DNMT1, DNMT3a, and DNMT3b) expression and DNA methylation, and how changes in DNA methylation may coordinate shifts in the expression of genes (BDNF, trkB and Arc) that regulate synaptic plasticity (DSD) and result in a predisposition to anxiety and alcoholism. Another approach is to examine the effects of systemic treatment with a newly identified trkB receptor agonist (7, 8-dihydroxyflavone) or intra-amygdaloid (CeA or MeA) infusion with BDNF on BDNF-trkB signaling (Erk1/2, CREB, Arc, and DSD) and on anxiety-like and alcohol-drinking behaviors using P and NP rats as an animal model. The proposed studies will provide new information on the epigenetic and cellular mechanisms of synaptic plasticity in the amygdala that may be involved in the comorbidity of anxiety and alcoholism. PUBLIC HEALTH RELEVANCE: Several factors, such as genetic traits, may be involved in the development of alcoholism. In addition, it has been shown that innate high anxiety levels promote higher alcohol consumption. This proposal will enhance our understanding of the brain epigenetic and signaling mechanisms associated with the comorbidity of anxiety and alcoholism and will identify novel cellular targets that can be used to develop future therapeutic agents in treating alcohol-abuse disorders with and without anxiety disorders.
Funding Period: 1997-03-01 - 2018-08-31
more information: NIH RePORT

Top Publications

  1. pmc Estrogen affects levels of Bcl-2 protein and mRNA in medial amygdala of ovariectomized rats
    Lu Fan
    Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA
    J Neurosci Res 86:3655-64. 2008
  2. pmc Neuroscience of alcoholism: molecular and cellular mechanisms
    Sachin Moonat
    Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA
    Cell Mol Life Sci 67:73-88. 2010
  3. pmc Neuropeptide Y signaling in the central nucleus of amygdala regulates alcohol-drinking and anxiety-like behaviors of alcohol-preferring rats
    Huaibo Zhang
    Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois 60612, USA
    Alcohol Clin Exp Res 34:451-61. 2010
  4. pmc The role of amygdaloid brain-derived neurotrophic factor, activity-regulated cytoskeleton-associated protein and dendritic spines in anxiety and alcoholism
    Sachin Moonat
    Department of Psychiatry, University of Illinois at Chicago and Jesse Brown VA Medical Center, 820 S Damen Avenue M C 151 Chicago, IL 60612, USA
    Addict Biol 16:238-50. 2011
  5. pmc Hetereogeneity of dose and time effects of estrogen on neuron-specific neuronal protein and phosphorylated cyclic AMP response element-binding protein in the hippocampus of ovariectomized rats
    Barclay W Bakkum
    Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois Illinois College of Optometry, Chicago, IL 60612, USA
    J Neurosci Res 89:883-97. 2011
  6. pmc The noradrenaline precursor L-DOPS reduces pathology in a mouse model of Alzheimer's disease
    Sergey Kalinin
    Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL, USA
    Neurobiol Aging 33:1651-63. 2012
  7. pmc Aberrant histone deacetylase2-mediated histone modifications and synaptic plasticity in the amygdala predisposes to anxiety and alcoholism
    Sachin Moonat
    Department of Psychiatry, University of Illinois at Chicago, IL 60612, USA
    Biol Psychiatry 73:763-73. 2013

Detail Information

Publications7

  1. pmc Estrogen affects levels of Bcl-2 protein and mRNA in medial amygdala of ovariectomized rats
    Lu Fan
    Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA
    J Neurosci Res 86:3655-64. 2008
    ..The E-induced increase in protein and mRNA levels of Bcl-2 in MeA may be important for neuroprotection in this region...
  2. pmc Neuroscience of alcoholism: molecular and cellular mechanisms
    Sachin Moonat
    Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA
    Cell Mol Life Sci 67:73-88. 2010
    ..This review outlines progressive neuroscience research into molecular and epigenetic mechanisms of alcoholism...
  3. pmc Neuropeptide Y signaling in the central nucleus of amygdala regulates alcohol-drinking and anxiety-like behaviors of alcohol-preferring rats
    Huaibo Zhang
    Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois 60612, USA
    Alcohol Clin Exp Res 34:451-61. 2010
    ..In this study, we investigated the molecular mechanisms by which NPY in the CeA regulates anxiety and alcohol drinking behaviors using alcohol-preferring (P) rats as an animal model...
  4. pmc The role of amygdaloid brain-derived neurotrophic factor, activity-regulated cytoskeleton-associated protein and dendritic spines in anxiety and alcoholism
    Sachin Moonat
    Department of Psychiatry, University of Illinois at Chicago and Jesse Brown VA Medical Center, 820 S Damen Avenue M C 151 Chicago, IL 60612, USA
    Addict Biol 16:238-50. 2011
    ....
  5. pmc Hetereogeneity of dose and time effects of estrogen on neuron-specific neuronal protein and phosphorylated cyclic AMP response element-binding protein in the hippocampus of ovariectomized rats
    Barclay W Bakkum
    Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois Illinois College of Optometry, Chicago, IL 60612, USA
    J Neurosci Res 89:883-97. 2011
    ..Our results indicate that responsiveness of cells expressing NeuN and pCREB to different EB regimens may vary depending on the specific region of the hippocampus...
  6. pmc The noradrenaline precursor L-DOPS reduces pathology in a mouse model of Alzheimer's disease
    Sergey Kalinin
    Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL, USA
    Neurobiol Aging 33:1651-63. 2012
    ..These data demonstrate the presence of LC stress in a robust mouse model of AD, and suggest that raising CNS NA levels could provide benefit in AD...
  7. pmc Aberrant histone deacetylase2-mediated histone modifications and synaptic plasticity in the amygdala predisposes to anxiety and alcoholism
    Sachin Moonat
    Department of Psychiatry, University of Illinois at Chicago, IL 60612, USA
    Biol Psychiatry 73:763-73. 2013
    ..However, the epigenetic basis and role of specific histone deacetylase (HDAC) isoforms in the genetic predisposition to anxiety and alcoholism is unknown...