PWZ-029, an inverse agonist selective for α5 GABAA receptors, improves object recognition, but not water-maze memory in normal and scopolamine-treated rats

Abstract

Inverse agonism at the benzodiazepine site of α5 subunit-containing GABAA receptors is an attractive approach for the development of putative cognition-enhancing compounds, which are still far from clinical application. Several ligands with binding and/or functional selectivity for α5 GABAA receptors have been synthesized and tested in a few animal models. PWZ-029 is an α5 GABAA selective inverse agonist whose memory enhancing effects were demonstrated in the passive avoidance task in rats and in Pavlovian fear conditioning in mice. In the present study we investigated the effects of PWZ-029 administration in novel object recognition test and Morris water maze, in normal and scopolamine-treated rats. All the three doses of PWZ-029 (2, 5 and 10 mg/kg) improved object recognition after the 24-h delay period, as shown by significant differences between the exploration times of the novel and old object, and the respective discrimination indices. PWZ-029 (2 mg/kg) also successfully reversed the 0.3 mg/kg scopolamine-induced deficit in recognition memory after the 1-h delay. In the Morris water maze test, PWZ-029 (5, 10 and 15 mg/kg) did not significantly influence swim patterns, either during five acquisition days or during the treatment-free probe trial. PWZ-029 (2, 5 and 10 mg/kg) also proved to be ineffective in the reversal of the 1 mg/kg scopolamine-induced memory impairment in the water maze. The present mixed results encourage use of a variety of tests and experimental conditions in order to increase the predictability of preclinical testing of selective α5 GABAA inverse agonists.

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

“…It is interesting to note that negative allosteric modulators (NAMs) at GABAA-Rs can also exert antidepressant [50] and pro-cognitive activity in recognition learning [51] and spatial memory [52], although reducing α5-GABAA-R function is predicted to worsen the pathologies. The putative pro-cognitive properties of both α5-NAMs and α5-PAMs are not mutually incompatible.…”

Selective Modulators of α₅-Containing GABA_A Receptors and their Therapeutic Significance

“…In a Pavlovian fear conditioning study, PWZ-029 notably reversed the scopolamine-induced impairment of contextual memory [54], in addition to improving the performance in novel object recognition test [56]. However, in contrast to most tested α 5 GABA A R negative modulators, PWZ-029 failed to improve cognitive performance in the Morris water maze model, either alone or in countering scopolamine-induced cognitive impairment in rats, prompting the need for further investigations to validate the cognition-enhancing properties of PWZ-029 [56].…”

Innovative mechanisms of action for pharmaceutical cognitive enhancement: A systematic review

“…GABAα5 blockers may provide a nootropic effect without the associated anxiogenic effects of general GABA inverse agonism (Koh et al, 2013;Milic et al, 2013).…”