title: Influence of benzodiazepine binding site ligands on fear-conditioned contextual memory.
abstract: Eight compounds that bind to the benzodiazepine binding site on the gamma-amino butyric acid(A) (GABA(A)) receptor were assessed for their influence on contextual memory, an aspect of memory affected in various cognitive disorders including Alzheimer's disease. Using a Pavlovian fear-conditioning paradigm, each ligand was evaluated in C57Bl/6 mice in regards to its direct affect on contextual memory and whether the ligand could attenuate scopolamine-induced contextual memory impairment. Of the eight ligands tested, one impaired contextual memory (agonist), six attenuated scopolamine-induced contextual memory impairment (inverse agonists), and one antagonized the ability of an inverse agonist to attenuate scopolamine-induced contextual memory impairment. Hence, further demonstrating the bi-directional influence benzodiazepine binding site ligands are able to exert on memory modulation. This study serves as an initial starting point in the development of pharmacological tools to be used in deciphering how GABA(A) receptors influence contextual memory.
authors.affiliation: Molecular Research Institute, 2495 Old Middlefield Way, Mountain View, CA 94043, USA. tim@purisima.molres.org
authors.forename: T M
authors.initials: TM
authors.lastname: DeLorey
authors.forename: R C
authors.initials: RC
authors.lastname: Lin
authors.forename: B
authors.initials: B
authors.lastname: McBrady
authors.forename: X
authors.initials: X
authors.lastname: He
authors.forename: J M
authors.initials: JM
authors.lastname: Cook
authors.forename: J
authors.initials: J
authors.lastname: Lameh
authors.forename: G H
authors.initials: GH
authors.lastname: Loew
mesh_terms: D000818:Animals; D001386:Azides / Q000494:pharmacology; D001569:Benzodiazepines / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000502:physiology*; D003292:Convulsants / Q000494:pharmacology; D005239:Fear / Q000502:physiology*; D005442:Flumazenil / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D019832:N-Methylscopolamine / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000378:metabolism; D012601:Scopolamine / Q000494:pharmacology; D012821:Silanes / Q000494:pharmacology; D014316:Tritium
chemical_list: C436004:2-(p-chlorophenyl)-4-(4-N-ethylamidepiperazinyl)quinoline; D001386:Azides; D002243:Carbolines; D003292:Convulsants; D018756:GABA Antagonists; D018757:GABA Modulators; D007093:Imidazoles; D008024:Ligands; D010879:Piperazines; D011804:Quinolines; D011963:Receptors, GABA-A; D012821:Silanes; C436003:ethyl-8-ethyl-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5a)(1,4)benzodiazepine-3-carboxylate; C436005:ethyl-8-trimethylsilyl-2-acetyl-12,12a-dihydro-9-oxo-9H,11H-azeto(2,1-c)imidazo(1,5a)-1,4-benzodiazepine; D014316:Tritium; D001569:Benzodiazepines; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D005442:Flumazenil; C042568:ZK 93426; C042957:Ro 15-4513; C043232:tert-butyl beta-carboline-3-carboxylate; D012601:Scopolamine; D019832:N-Methylscopolamine