The multicomponantal GABA receptor-ionophore complex is a site of action for a variety of centrally acting drugs. This complex is composed of a least GABA receptor sites, benzodiazepine sites and picrotoxin sites. This proposal seeks to characterize the convulsant and anticonvulsant receptors on this complex using radioligand and behavioral studies. The major aims include: i) determining the effect of convulsants, anticonvulsants and GABA agonists on the dissociation kinetics of (35S)t-butyl-bicyclophosphorothionate (TBPT), a ligand which binds to the picrotoxin site on the GABA receptor complex; ii) determine if anticonvulsants and/or hypnotic effects of barbiturates are mediated via GABA receptor system; iii) determine the effect of chronic barbiturate administration during its withdrawal and on the binding constants of GABA, TBPT and flunitrazepam;; iv) characterize GABA pharmacology by studying the effect of modulators of GABA transmission in the absence and presence of GABA on 35C1 fluxes; and v) determine if GABA receptor populations are interconvertible. Spinal cord cultures will provide us with a system to correlate binding studies with GABA receptor function in vitro. Further, cultures can be grown in the presence of various modulators to determine up or down regulation of receptors. Preliminary results indicate that convulsants and nonbenzodiazepine anticonvulsant/hypnotics bind to two distinct but coupled sites at the GABA receptor complex. These studies are aimed at increasing our understanding of the major inhibitory transmitters mediated by GABA and define the molecular mechanism of drug action at this receptor complex. GABAergic transmission has relevance to epilepsy, Huntington's chorea, anxiety and hypertension. A clearer understanding of the GABAergic transmission is a prerequisite to our understanding of normal biology and in the rational development of drugs for disorders involving a dysfunction of the GABA system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS015339-09
Application #
3396172
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1979-07-01
Project End
1990-11-30
Budget Start
1987-12-01
Budget End
1988-11-30
Support Year
9
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Type
School of Medicine & Dentistry
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Mehta, A K; Ticku, M K (1999) An update on GABAA receptors. Brain Res Brain Res Rev 29:196-217
Mhatre, M C; Ticku, M K (1998) Caloric restriction retards the aging associated changes in gamma-aminobutyric acidA receptor gene expression in rat cerebellum. Brain Res Mol Brain Res 54:270-5
Yu, R; Hay, M; Ticku, M K (1996) Chronic neurosteroid treatment attenuates single cell GABAA response and its potentiation by modulators in cortical neurons. Brain Res 706:160-2
Yu, R; Ticku, M K (1995) Chronic neurosteroid treatment decreases the efficacy of benzodiazepine ligands and neurosteroids at the gamma-aminobutyric acidA receptor complex in mammalian cortical neurons. J Pharmacol Exp Ther 275:784-9
Yu, R; Ticku, M K (1995) Effects of chronic pentobarbital treatment on the GABAA receptor complex in mammalian cortical neurons. J Pharmacol Exp Ther 275:1442-6
Yu, R; Ticku, M K (1995) Chronic neurosteroid treatment produces functional heterologous uncoupling at the gamma-aminobutyric acid type A/benzodiazepine receptor complex in mammalian cortical neurons. Mol Pharmacol 47:603-10
Hu, X J; Ticku, M K (1994) Chronic benzodiazepine agonist treatment produces functional uncoupling of the gamma-aminobutyric acid-benzodiazepine receptor ionophore complex in cortical neurons. Mol Pharmacol 45:618-25
Mhatre, M C; Ticku, M K (1994) Chronic GABA treatment downregulates the GABAA receptor alpha 2 and alpha 3 subunit mRNAS as well as polypeptide expression in primary cultured cerebral cortical neurons. Brain Res Mol Brain Res 24:159-65
Hu, X J; Ticku, M K (1994) Development pattern of the GABAA-benzodiazepine receptor ionophore complex in primary cultures of cortical neurons. Brain Res Dev Brain Res 80:137-40
Mehta, A K; Ticku, M K (1993) Ethanol- and diazepam-withdrawal hyperlocomotion is not due to 5-HT3 receptor stimulation. Pharmacol Biochem Behav 45:755-7

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