Cognition-impairing effects of benzodiazepine-type drugs: Role of GABAA receptor subtypes in an executive function task in rhesus monkeys

The present studies evaluated the role of alpha 1 and alpha 5 subunit-containing GABA(A) receptors (alpha 1GABA(A) and alpha 5GABA(A) 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 9-17 years old) were trained on the object retrieval with detours CORD) 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 alpha 1GABA(A)-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 alpha 1GABA(A)-preferring antagonist, beta CCT, whereas the alpha 5GABA(A)-preferring antagonist XLi-093 blocked the effects of triazolam but not zolpidem. While these findings suggest a role for both alpha 1GABA(A) and alpha 5GABA(A) receptor mechanisms, alpha 1GABA(A) receptor mechanisms appear to be sufficient for impairments in executive function induced by BZ-type drugs. (C) 2012 Elsevier Inc. All rights reserved.