title: GABAA receptors and benzodiazepines: a role for dendritic resident subunit mRNAs.
abstract: This review is designed to describe the evolution of the seminal observation made simultaneously in 1975 by Dr. W. Haefely's laboratory (Hoffman La Roche, Basel, Switzerland) and in the Laboratory of Preclinical Pharmacology (NIH, St. Elizabeths Hospital, Washington DC), that benzodiazepine action was mediated by a modulation of GABA action at GABA(A) receptors. In fact, our suggestion was that the benzodiazepine receptor was "a receptor on a receptor" and that this receptor was GABA(A). Needless to say, this suggestion created opposition, but we did not abandon the original idea, in fact, as shown in this review, there is now universal agreement with our hypothesis on the mode of action of benzodiazepines. Hence, this review deals with the allosteric modulation of GABA(A) receptors by benzodiazepines, the role of GABA(A) receptors and benzodiazepine structure diversities in this modulation, and describes the results of our attempts to establish a benzodiazepine (imidazenil) devoid of tolerance, withdrawal symptoms, and changes in the expression of GABA(A) receptor subunits during tolerance. It also deals with the idea that the synthesis of GABA(A) receptor subunits triggered by tolerance resides in dendrites and spines where mRNAs and the apparatus for this translation is located. New analytic procedures may foster progress in the understanding of tolerance to and withdrawal from benzodiazepines.
authors.affiliation: University of Illinois at Chicago, Department of Psychiatry, Psychiatric Institute, 1601 W Taylor St, Chicago, IL 60612, USA. costa@psych.uic.edu
authors.forename: E
authors.initials: E
authors.lastname: Costa
authors.forename: J
authors.initials: J
authors.lastname: Auta
authors.forename: D R
authors.initials: DR
authors.lastname: Grayson
authors.forename: K
authors.initials: K
authors.lastname: Matsumoto
authors.forename: G D
authors.initials: GD
authors.lastname: Pappas
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: A
authors.initials: A
authors.lastname: Guidotti
mesh_terms: D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D001569:Benzodiazepines / Q000145:classification / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive; D018118:Chloride Channels / Q000187:drug effects; D003712:Dendrites / Q000187:drug effects* / Q000378:metabolism; D003975:Diazepam / Q000493:pharmacokinetics; D004361:Drug Tolerance / Q000235:genetics / Q000502:physiology; D018757:GABA Modulators / Q000493:pharmacokinetics; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D019579:Neocortex / Q000166:cytology / Q000378:metabolism; D010599:Pharmacokinetics; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000502:physiology; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013375:Substance Withdrawal Syndrome
chemical_list: D018118:Chloride Channels; D018757:GABA Modulators; D007093:Imidazoles; D007527:Isoenzymes; D021122:Protein Subunits; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D001569:Benzodiazepines; C082661:imidazenil; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D003975:Diazepam