The oligomeric GABA/A receptor-ionophore complex belongs to ligand-gated ion-channel gene family, and it is a site of action for a variety of centrally acting drugs including ethanol. Recent molecular biological studies have demonstrated heterogeneity of GABA/A receptors, especially in terms of the distribution of alpha subunits in the CNS. The proposal is an extension of ongoing studies aimed at understanding and defining the involvement of GABA receptor system in the actions of ethanol. This will be achieved by using radioligand binding studies, ion flux studies, photoaffinity labeling, and measuring mRNA levels by Northern blot analysis. These studies will be conducted in parallel in well characterized mammalian cultured spinal cord neurons (alpha3, alpha2 and/or alpha 4 abundant) and cortical neurons (alpha1 abundant). We will determine if ethanol modulates GABA/A ergic transmission in a similar or different ways in these two varied forms of GABA/A receptors. Studies are also proposed to determine if chronic ethanol induced upregulation of inverse agonist benzodiazepine binding sites can be correlated with changes in mRNA levels of different subunits (alpha, beta, gamma2) of GABA/A receptors in spinal cord and cortical neurons. Similar chronic ethanol studies will be conducted in rat brain regions. Additionally, we will determine if GABA/B receptors are involved in ethanol modulation of GABA/A ergic transmission or in the actions of ethanol. This will be investigated by determining: a) if GABA/3B receptor agonists or antagonists modulate ethanol interactions with GABA-induced Cl-influx; b) if GABA/B receptor coupled G-proteins are involved in ethanol's effect on GABA/A mediated responses; and c) if ethanol has any facilitatory effect on GABA/B receptor mediated presynaptic or postsynaptic effects, using new 86Rb-flux assays, developed in our laboratory. The proposed studies are aimed at increasing our understanding of the involvement of two varied forms of GABA/A receptor system and GABA/B receptors in the actions of ethanol.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
2R01AA004090-08
Application #
3108875
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1983-04-01
Project End
1996-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
8
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Mehta, A K; Ticku, M K (2001) Unsulfated and sulfated neurosteroids differentially modulate the binding characteristics of various radioligands of GABA(A) receptors following chronic ethanol administration. Neuropharmacology 40:668-75
Mehta, A K; Ticku, M K (1999) Prevalence of the GABAA receptor assemblies containing alpha1-subunit in the rat cerebellum and cerebral cortex as determined by immunoprecipitation: lack of modulation by chronic ethanol administration. Brain Res Mol Brain Res 67:194-9
Mehta, A K; Ticku, M K (1999) An update on GABAA receptors. Brain Res Brain Res Rev 29:196-217
Kalluri, H S; Mehta, A K; Ticku, M K (1998) Up-regulation of NMDA receptor subunits in rat brain following chronic ethanol treatment. Brain Res Mol Brain Res 58:221-4
Mehta, A K; Ticku, M K (1998) Chronic ethanol administration alters the modulatory effect of 5alpha-pregnan-3alpha-ol-20-one on the binding characteristics of various radioligands of GABAA receptors. Brain Res 805:88-94
Sircar, R; Follesa, P; Ticku, M K (1996) Postnatal phencyclidine treatment differentially regulates N-methyl-D-aspartate receptor subunit mRNA expression in developing rat cerebral cortex. Brain Res Mol Brain Res 40:214-20
Follesa, P; Ticku, M K (1995) Chronic ethanol treatment differentially regulates NMDA receptor subunit mRNA expression in rat brain. Brain Res Mol Brain Res 29:99-106
Mhatre, M; Ticku, M K (1994) Chronic ethanol treatment upregulates the GABA receptor beta subunit expression. Brain Res Mol Brain Res 23:246-52
Mehta, A K; Ticku, M K (1994) Ethanol enhancement of GABA-induced 36Cl- influx does not involve changes in Ca2+. Pharmacol Biochem Behav 47:355-7
Mhatre, M C; Ticku, M K (1993) Alcohol: effects on GABAA receptor function and gene expression. Alcohol Alcohol Suppl 2:331-5

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