Abstract

The central nervous system (CNS) site of action of the atypical benzodiazepine (BZ), Ro5 4864 (4'-chlorodiazepam), is not known. Some of the prominent CNS mediated effects of Ro5 4864 include convulsions and anxiogenic effects. Preliminary studies from our laboratory provide evidence for a novel binding site for Ro5 4864 in rat brain that is linked to a GABAA/BZ receptor and a C1- ionophore. Coupled with previous behavioral and electrophysiological evidence supporting such a link, the hypothesis that a functionally relevant and unique Ro5 4864 site located on a GABA receptor-C1- ionophore complex exists in the mammalian CNS can be proposed.
The specific aims of this proposal are to characterize and determine the functional significance of this drug receptor.
These aims will be accomplished by 1) in vitro characterization of binding site properties to determine if the basic criteria for receptor identification can be met; 2) evaluation of the """"""""response"""""""" to Ro5 4864 binding site activation; 3) identification of the functional consequences of Ro5 4864 binding site activation in vivo and 4) cloning the gene(s) encoding the Ro5 4864 site. The pharmacological characterization of this GABAA receptor-C1- ionophore linked binding site may provide the framework for the development of ligands for this site that may be of therapeutic benefit in the treatment of anxiety and seizure disorders.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
7R29NS024645-05
Application #
3476741
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1988-02-01
Project End
1993-06-30
Budget Start
1992-05-01
Budget End
1993-06-30
Support Year
5
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
University of California Irvine
Department
Type
Schools of Medicine
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697

  Publications

McCauley, L D; Park, C H; Lan, N C et al. (1995) Benzodiazepines and peptides stimulate pregnenolone synthesis in brain mitochondria. Eur J Pharmacol 276:145-53
Lan, N C; Chen, J S; Johnson, D et al. (1995) Differential effects of 4'-chlorodiazepam on expressed human GABAA receptors. J Neurochem 64:684-8
Finn, D A; Gee, K W (1994) The estrus cycle, sensitivity to convulsants and the anticonvulsant effect of a neuroactive steroid. J Pharmacol Exp Ther 271:164-70
Finn, D A; Gee, K W (1993) A comparison of Ro 16-6028 with benzodiazepine receptor 'full agonists' on GABAA receptor function. Eur J Pharmacol 247:233-7
Finn, D A; Gee, K W (1993) The influence of estrus cycle on neurosteroid potency at the gamma-aminobutyric acidA receptor complex. J Pharmacol Exp Ther 265:1374-9
McCauley, L D; Lan, N C; Tomich, J M et al. (1992) Peripheral-type benzodiazepine receptors and the regulation of steroidogenesis in rat brain mitochondria. Adv Biochem Psychopharmacol 47:143-7
Gee, K W; Lan, N C; Bolger, M B et al. (1992) Pharmacology of a GABAA receptor coupled steroid recognition site. Adv Biochem Psychopharmacol 47:111-7
Gee, K W; Lan, N C (1991) Gamma-aminobutyric acidA receptor complexes in rat frontal cortex and spinal cord show differential responses to steroid modulation. Mol Pharmacol 40:995-9
Wieland, S; Lan, N C; Mirasedeghi, S et al. (1991) Anxiolytic activity of the progesterone metabolite 5 alpha-pregnan-3 alpha-o1-20-one. Brain Res 565:263-8
Belelli, D; Lan, N C; Gee, K W (1990) Anticonvulsant steroids and the GABA/benzodiazepine receptor-chloride ionophore complex. Neurosci Biobehav Rev 14:315-22

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