title: Cognition-impairing effects of benzodiazepine-type drugs: role of GABAA receptor subtypes in an executive function task in rhesus monkeys.
abstract: The present studies evaluated the role of α1 and α5 subunit-containing GABAA receptors (α1GABAA and α5GABAA receptors, respectively) in the ability of benzodiazepine (BZ)-type drugs to alter performance in the cognitive domain of executive function. Five adult female rhesus monkeys (ages of 9-17years old) were trained on the object retrieval with detours (ORD) task of executive function. For the ORD task, the monkeys were required to retrieve food items from a clear box with one open end that was rotated to different positions along with varying placements of food. When the non-selective BZ triazolam and the α1GABAA-preferring agonists zolpidem and zaleplon were evaluated in the ORD task, deficits in performance occurred at doses that did not increase the latency of monkeys to initiate responding and/or increase the percentage of reaches that were incorrect (i.e., reaches in which food was not obtained). Cognition-impairing effects of triazolam and zolpidem in ORD were blocked by the α1GABAA-preferring antagonist, βCCT, whereas the α5GABAA-preferring antagonist XLi-093 blocked the effects of triazolam but not zolpidem. While these findings suggest a role for both α1GABAA and α5GABAA receptor mechanisms, α1GABAA receptor mechanisms appear to be sufficient for impairments in executive function induced by BZ-type drugs.
authors.affiliation: Division of Neuroscience, New England Primate Research Center, Harvard Medical School, Box 9102, 1 Pine Hill Drive, Southborough, MA 01772, USA. leah_makaron@hms.harvard.edu
authors.forename: Leah
authors.initials: L
authors.lastname: Makaron
authors.forename: Casey A
authors.initials: CA
authors.lastname: Moran
authors.forename: Ojas
authors.initials: O
authors.lastname: Namjoshi
authors.forename: Sundari
authors.initials: S
authors.lastname: Rallapalli
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
authors.forename: James K
authors.initials: JK
authors.lastname: Rowlett
mesh_terms: D000081:Acetamides / Q000009:adverse effects; D000818:Animals; D014151:Anti-Anxiety Agents / Q000009:adverse effects; D001569:Benzodiazepines / Q000009:adverse effects*; D001570:Benzodiazepinones / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D056344:Executive Function / Q000187:drug effects* / Q000502:physiology; D005260:Female; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000009:adverse effects; D007093:Imidazoles / Q000494:pharmacology; D008253:Macaca mulatta / Q000502:physiology* / Q000523:psychology*; D011725:Pyridines / Q000009:adverse effects; D011743:Pyrimidines / Q000009:adverse effects; D011963:Receptors, GABA-A / Q000145:classification* / Q000187:drug effects* / Q000502:physiology; D014229:Triazolam / Q000009:adverse effects; D000077334:Zolpidem
chemical_list: C480603:1,3-bis(8-ethynyl-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5-a)(1,4)benzodiazepine-3-carboxy)propyl diester; D000081:Acetamides; D014151:Anti-Anxiety Agents; D001570:Benzodiazepinones; D002243:Carbolines; D058787:GABA-A Receptor Antagonists; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D011725:Pyridines; D011743:Pyrimidines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D014229:Triazolam; D000077334:Zolpidem; C043232:tert-butyl beta-carboline-3-carboxylate; C085665:zaleplon