Regional distribution of a Ro5 4864 binding site that is functionally coupled to the γ-aminobutyric acid/benzodiazepine receptor complex in rat brain

K. W. Gee, R. E. Brinton, B. S. McEwen

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

The hypothesis that a novel drug binding site linked to a γ-aminobutyric acid (GABA)-regulated chloride ionophore mediates the excitatory effects of the atypical benzodiazepine (BZ) Ro5 4864 is further evaluated in the present study. Dose-dependent inhibition of [3H]flunitrazepam to the central BZ receptor in rat cerebral cortex by the cage convulsant t-butylbicyclophosphorotionate (TBPS) is modulated by Ro5 4864 and the isoquinoline PK 11195 in a manner consistent with their reported pro/anti-convulsant effects. The ability of Ro5 4864 to enhance the binding of [35S]TBPS to a GABA-regulated chloride ionophore in rat cortex is unchanged after the irreversible labeling of the central BZ receptor by the photoaffinity label Ro15 4513. Together, these observations further suggest that 1) the effect of Ro5 4864 on [35S]TBPS is not mediated by the central BZ receptor and 2) the Ro5 4864 binding site is allosterically coupled to the GABA/BZ receptor-chloride ionophore complex in rat cerebral cortex. Anatomical localization of Ro5 4864-stimulated [35S]TBPS binding in rat brain by autoradiography reveals a distribution of chloride ionophore-coupled Ro5 4864 sites which is in many instances similar to that of the GABA/BZ receptor-chloride ionophore complex. These studies lend additional support to the postulate that this drug binding site represents an additional locus for the regulation of GABAergic neurotransmission in the central nervous system.

Original languageEnglish (US)
Pages (from-to)379-383
Number of pages5
JournalJournal of Pharmacology and Experimental Therapeutics
Volume244
Issue number1
StatePublished - 1988
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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