Alterations in serotonergic function have been implicated in alcohol dependence. This is based on studies of serotonin (5HT), its metabolite 5-hydroxyindoleacetic acid (5HIAA), and 5HT receptor subtypes in the brain of alcohol-dependent and withdrawn rats. Anxiogenic behaviors are present at an early stage of alcohol withdrawal. Behavioral studies indicate that 5HT2A/2C receptors are involved in producing the anxiogenic behaviors occurring during ethanol withdrawal. The role of the 5HT2A/2C receptor system, i.e., 5HT 2A/2C receptor density and mRNA levels, 5HT2A/2C receptor-linked phosphoinositide (PI) hydrolysis, and gene expression (MRNA levels) and translation (Immunolabeling) of the phospholipase C (PLC)-B isozyme, in anxiety during ethanol withdrawal, is largely unknown. The proposed studies will examine the role of the serotonergic mechanisms, more specifically the 5HT 2A/2C receptor system, in anxiety related to ethanol withdrawal. The major objectives of the proposed studies are A): To examine whether the time-course for development of anxiety during ethanol withdrawal is associated with the time-course for: 1) changes in 5HT2A and 5HT2C receptors; 2) changes in 5HT2A/2C receptor-linked PI hydrolysis; 3) changes in steps beyond the 5HT2A/2C receptors, i.e., gene expression (mRNA levels) and translation (immunolabeling) of the PLC-B isozyme; 4) changes in gene expression (mRNA levels) of 5HT2A/2C receptors during ethanol withdrawal. These biochemical measures will be performed in the frontal cortex, the hippocampus, and the amygdala of chow and liquid diet-fed control and ethanol-withdrawn (0, 12, 24, and 72 hrs after 15 days of ethanol treatment) rats; and B): To examine if chronic treatment with a 5HT2A/2C receptor system (5HT2A/2C receptor binding and mRNA levels, 5HT2A/2C receptor-linked PI hydrolysis, and mRNA levels and immunolabeling of the PLC-B isozyme) in the frontal cortex, the hipppocampus, and the amygdala during ethanol withdrawal and also blocks anxiety as measured by the elevated plus maze test (open arm activity). Thus, the proposed research will provide a better understanding of the molecular mechanisms for the regulation of the 5HT2A/2C receptor system in alcohol dependence and may facilitate the development of specific serotonergic drugs that can be used in the prevention and treatment of specific ethanol withdrawal symptoms, e.g., anxiety.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AA010005-04
Application #
6163739
Study Section
Special Emphasis Panel (ZRG4-ALTX-3 (01))
Project Start
1997-03-01
Project End
2002-02-28
Budget Start
2000-03-01
Budget End
2001-02-28
Support Year
4
Fiscal Year
2000
Total Cost
$90,174
Indirect Cost
Name
University of Illinois at Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Gavin, David P; Kusumo, Handojo; Zhang, Huaibo et al. (2016) Role of Growth Arrest and DNA Damage-Inducible, Beta in Alcohol-Drinking Behaviors. Alcohol Clin Exp Res 40:263-72
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
Pandey, Subhash C (2016) A Critical Role of Brain-Derived Neurotrophic Factor in Alcohol Consumption. Biol Psychiatry 79:427-9
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
Gavin, David P; Kusumo, Handojo; Sharma, Rajiv P et al. (2015) Gadd45b and N-methyl-D-aspartate induced DNA demethylation in postmitotic neurons. Epigenomics 7:567-79
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
Krishnan, Harish R; Sakharkar, Amul J; Teppen, Tara L et al. (2014) The epigenetic landscape of alcoholism. Int Rev Neurobiol 115:75-116

Showing the most recent 10 out of 21 publications