The gamma-aminobutyric acid type A receptor (GABAA-R) has been extensively implicated as a key component of the mechanism of action of ethanol. However, the contribution of individual subunits of the GABAA-R to ethanol-related behaviors has not been adequately addressed. The alpha4 subunit of the GABAA-R has specifically been implicated in modulating behavioral hyperexcitibility in a variety of experimental conditions including ethanol dependence and withdrawal. The use of sophisticated transgenic and gene targeting technology now allows hypotheses to be tested in an unambiguous manner, using precise molecular tools within the context of the whole animal. By testing a variety of mouse models with altered regional and temporal patterns of expression of alpha4 on a battery of molecular, cellular, and behavioral assays, we have the opportunity to elucidate the contribution of the alpha4 subunit to clinically relevant ethanol-related behaviors. We believe these studies provide an integrated approach toward our goal of understanding how ethanol exerts its effects in the central nervous system. To accomplish our goal, the following specific aims are proposed: A1. Create and characterize a transgenic mouse line that overexpresses a tetracycline regulated GABAA-R alpha4 subunit. A2. Create and characterize genetically engineered mice that harbor a ubiquitous knockout of the alpha4 subunit of the GABAA-R. A3. Create and characterize novel transgenic mouse lines that direct inducible, neuron-specific gene recombination. A4. Create and characterize an inducible, neuron-specific GABAAR alpha4 knockout mouse line. A5. Analyze these genetically manipulated animals with a battery of tests to assess basic physiology, behavior, and phenotypic alterations in ethanol-induced behaviors.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA013004-02
Application #
6623602
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Neuhold, Lisa
Project Start
2002-05-01
Project End
2007-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
2
Fiscal Year
2003
Total Cost
$369,641
Indirect Cost
Name
University of Pittsburgh
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Peng, Zechun; Zhang, Nianhui; Chandra, Dave et al. (2014) Altered localization of the ? subunit of the GABAA receptor in the thalamus of ?4 subunit knockout mice. Neurochem Res 39:1104-17
Iyer, Sangeetha V; Chandra, Dave; Homanics, Gregg E (2014) GABAA-R ?4 subunits are required for the low dose locomotor stimulatory effect of alphaxalone, but not for several other behavioral responses to alphaxalone, etomidate or propofol. Neurochem Res 39:1048-56
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Harrison, Susan J; Nishinakamura, Ryuichi; Jones, Kevin R et al. (2012) Sall1 regulates cortical neurogenesis and laminar fate specification in mice: implications for neural abnormalities in Townes-Brocks syndrome. Dis Model Mech 5:351-65
Chang, Ki-Young; Park, Young-Gyun; Park, Hye-Yeon et al. (2011) Lack of CaV3.1 channels causes severe motor coordination defects and an age-dependent cerebellar atrophy in a genetic model of essential tremor. Biochem Biophys Res Commun 410:19-23
Iyer, Sangeetha V; Benavides, Rodrigo A; Chandra, Dev et al. (2011) ?4-Containing GABA(A) Receptors are Required for Antagonism of Ethanol-Induced Motor Incoordination and Hypnosis by the Imidazobenzodiazepine Ro15-4513. Front Pharmacol 2:18
Moore, M D; Cushman, J; Chandra, D et al. (2010) Trace and contextual fear conditioning is enhanced in mice lacking the alpha4 subunit of the GABA(A) receptor. Neurobiol Learn Mem 93:383-7
Halonen, Lauri M; Sinkkonen, Saku T; Chandra, Dev et al. (2009) Brain regional distribution of GABA(A) receptors exhibiting atypical GABA agonism: roles of receptor subunits. Neurochem Int 55:389-96
Harrison, Susan J; Nishinakamura, Ryuichi; Monaghan, A Paula (2008) Sall1 regulates mitral cell development and olfactory nerve extension in the developing olfactory bulb. Cereb Cortex 18:1604-17
Jia, Fan; Chandra, Dev; Homanics, Gregg E et al. (2008) Ethanol modulates synaptic and extrasynaptic GABAA receptors in the thalamus. J Pharmacol Exp Ther 326:475-82

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