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

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.

► PWZ-029 is an α5 GABAA selective inverse agonist. ► We tested PWZ-029, on its own and with scopolamine, in two memory paradigms. ► It improved object recognition in the novel object recognition test. ► PWZ-029 was ineffective in the Morris water maze test. ► Testing of putative procognitive compounds needs use of a variety of models.