There has been conflicting data concerning the effects of ethanol on GABA/A receptor function. While biochemical and behavioral investigations have been supportive of ethanol influencing GABA responses, electrophysiological studies have provided mixed results with some investigations observing an enhancement of GABA inhibition by ethanol and others reporting no effect. Recently, our laboratory observed that ethanol enhanced GABA responses in the medial septum but not in the lateral septum. To explain the differences at these sites and the literature controversy, we propose that the cellular action of ethanol on GABA/A responses depends upon a specific molecular composition of the GABA/A receptor complex which varies at different sites in brain.
Three specific aims are proposed to explore this hypothesis. The first Specific Aim will identify the specific subunit composition of the GABA receptor complexes in the lateral and medial septum. This will be accomplished by measuring mRNA for the GABA/A subunits at these brain sites.
The Second Aim will determine the cellular location of sites having mRNA for the GABA/A receptor like that for the medial or lateral septum. In situ hybridization of the appropriate mRNA will be used to make this determination. Finally, the third Specific Aim will characterize electrophysiologically the effect of ethanol on responses to iontophoretically applied GABA at sites defined with in-situ hybridization as having GABA/A receptors like either the medial or lateral septum. This latter study will provide a direct test of our hypothesis. To complement the electrophysiological studies, various ligands binding to the GABA complex will be tested at the sites investigated electrophysiologically. This autoradiographic evaluation will provide an alternative approach by which ethanol's actions on GABA/A receptors can be predicted. This work is expected to clarify the actions of ethanol on CNS function.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA009122-03
Application #
2045325
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1992-02-01
Project End
1997-01-31
Budget Start
1994-02-01
Budget End
1995-01-31
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Yang, X; Criswell, H E; Breese, G R (2000) Ethanol modulation of gamma-aminobutyric acid (GABA)-mediated inhibition of cerebellar Purkinje neurons: relationship to GABAb receptor input. Alcohol Clin Exp Res 24:682-90
Yang, X; Criswell, H E; Breese, G R (1999) Action of ethanol on responses to nicotine from cerebellar Purkinje neurons: relationship to methyllycaconitine (MLA) inhibition of nicotine responses. Neurochem Int 35:185-94
Criswell, H E; McCown, T J; Ming, Z et al. (1999) Interactive role for neurosteroids in ethanol enhancement of gamma-aminobutyric acid-gated currents from dissociated substantia nigra reticulata neurons. J Pharmacol Exp Ther 291:1054-9
Yang, X; Criswell, H E; Breese, G R (1999) Action of ethanol on responses to nicotine from cerebellar interneurons and medial septal neurons: relationship to methyllycaconitine inhibition of nicotine responses. Alcohol Clin Exp Res 23:983-90
Yang, X; Knapp, D J; Criswell, H E et al. (1998) Action of ethanol and zolpidem on gamma-aminobutyric acid responses from cerebellar Purkinje neurons: relationship to beta-adrenergic receptor input. Alcohol Clin Exp Res 22:1655-61
Criswell, H E; McCown, T J; Moy, S S et al. (1997) Action of zolpidem on responses to GABA in relation to mRNAs for GABA(A) receptor alpha subunits within single cells: evidence for multiple functional GABA(A) isoreceptors on individual neurons. Neuropharmacology 36:1641-52
Xiao, X; McCown, T J; Li, J et al. (1997) Adeno-associated virus (AAV) vector antisense gene transfer in vivo decreases GABA(A) alpha1 containing receptors and increases inferior collicular seizure sensitivity. Brain Res 756:76-83
Yang, X; Criswell, H E; Simson, P et al. (1996) Evidence for a selective effect of ethanol on N-methyl-d-aspartate responses: ethanol affects a subtype of the ifenprodil-sensitive N-methyl-d-aspartate receptors. J Pharmacol Exp Ther 278:114-24
Yang, X; Criswell, H E; Breese, G R (1996) Nicotine-induced inhibition in medial septum involves activation of presynaptic nicotinic cholinergic receptors on gamma-aminobutyric acid-containing neurons. J Pharmacol Exp Ther 276:482-9
Criswell, H E; Simson, P E; Knapp, D J et al. (1995) Effect of zolpidem on gamma-aminobutyric acid (GABA)-induced inhibition predicts the interaction of ethanol with GABA on individual neurons in several rat brain regions. J Pharmacol Exp Ther 273:526-36

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