Modulation of GABA-stimulated Cl- flux by a benzodiazepine agonist and an 'inverse agonist' after chronic flurazepam treatment.
Rats treated one week with flurazepam were killed while still on the drug or 48 h after termination of drug treatment. The brain 'microsac' preparation derived from the cerebral cortices was used for studying the GABA-stimulated chloride influx. There was no significant change in the basal or GABA-stimulated influx between control and treated groups. However, the effect of flunitrazepam to enhance 10 microM GABA-stimulated influx was significantly reduced, indicating tolerance. Methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3- carboxylate (DMCM), an 'inverse agonist' at benzodiazepine receptors, dose dependently inhibited 50 microM GABA-stimulated influx; chronic treatment did not alter the effect of DMCM. This study demonstrates that one week treatment with flurazepam produces tolerance to benzodiazepines without any change in the effect of GABA or DMCM. This indicates that GABA and benzodiazepine sites are differently modulated after chronic treatment with benzodiazepines. However, since both benzodiazepine and DMCM act on the same receptors it appears that the different 'domains' on the benzodiazepine receptor are differently altered during chronic treatment.
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Department of Pharmacology, Medical College of Ohio, Toledo 43699-0008.
Rosenberg
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Chiu
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D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D001640:Bicuculline / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005479:Flurazepam / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D002243:Carbolines; D002712:Chlorides; D001569:Benzodiazepines; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D005680:gamma-Aminobutyric Acid; D005479:Flurazepam; D001640:Bicuculline