Relationship of agonist efficacy to changes in GABA sensitivity and anticonvulsant tolerance following chronic benzodiazepine ligand exposure.
Benzodiazepine ligands of differing efficacy including the agonist, diazepam, the partial agonist, Ro 16-6028 and the antagonist, Ro 15-1788, were administered in vivo to rats continuously for 3 weeks. The magnitude of change in various measures of GABA sensitivity could be correlated directly with increasing agonist efficacy: maximal changes were seen following chronic treatment with diazepam, intermediate changes were seen following the partial agonist Ro 16-6028 and no changes were observed following chronic Ro 15-1788 administration. The magnitude of change could also be correlated with increasing potential for tolerance development to anticonvulsant efficacy following chronic exposure to these benzodiazepine ligands.
Hernandez
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TD
Yale University School of Medicine, Department of Psychiatry, Abraham Ribicoff Research Facilities and Connecticut Mental Health Center, New Haven, CT.
Heninger
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Wilson
M A
MA
Gallager
D W
DW
D000818:Animals; D000927:Anticonvulsants; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D001640:Bicuculline / Q000378:metabolism / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects; D003975:Diazepam / Q000494:pharmacology; D004361:Drug Tolerance; D004594:Electrophysiology; D005442:Flumazenil / Q000494:pharmacology; D008297:Male; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D000927:Anticonvulsants; D001570:Benzodiazepinones; D001569:Benzodiazepines; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; C054626:bretazenil; D003975:Diazepam; D001640:Bicuculline