Evidence for a γ-aminobutyric acid (GABA) mediation in the benzodiazepine inhibition of the release of Met5-enkephalin elicited by depolarization

L. G. Harsing, H. Y.T. Yang, E. Costa

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The Met5-enkephalin (ME) content of perfused striatal slices decreased by 54% after 66 min of perfusion. The addition to the superfusion fluid of an inhibitor of ME metabolism (Phe-Ala, 0.1 mM) reduced the decrease of the ME content of striatal slices during the superfusion. At the beginning of the superfusion the ME efflux was rapid; it became progressively slower and leveled off to 20 fmol/mg of protein per min between 36 and 66 min of perfusion. This rate was doubled by the addition to the perfusion fluid of depolarizing concentrations of KCl (47 mM). The rate of ME efflux during depolarization was Ca++-dependent. The amount of ME detected in the perfusate was greater when the slices were perfused with Phe-Ala (0.1 mM). Micromolar concentrations of diazepam and flunitrazepam failed to change the basal rates of ME efflux, but inhibited in a concentration-dependent manner the efflux of ME which was stimulated by depolarization. This action of benzodiazepine was mimicked by muscimol and THIP [two analogs of γ-aminobutyric acid (GABA) with rigid conformation] and was antagonized by picrotoxin (5 μM) which impairs the function of GABA receptors. When the slices were prepared from striatum of rats receiving doses of isoniazid, which reduced GABA content to about 60%, diazepam but not muscimol failed to reduce the efflux of ME elicited by depolarization. It is concluded that the inhibition of ME efflux during depolarization elicited by diazepam requires a certain amount of GABA and the availability of GABA receptors, the similar action of muscimol requires only the availability of GABA receptors.

Original languageEnglish
Pages (from-to)616-620
Number of pages5
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
Publication statusPublished - Jan 1 1982

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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