RO4938581, a novel cognitive enhancer acting at GABAA a5 subunit-containing receptors

Rationale: GABAA a5 subunit-containing receptors are primarily expressed in the hippocampus and their role in learning and memory has been demonstrated recently by both genetic and pharmacological approaches. Objectives: The objective of the study is to evaluate the cognitive effects of a novel GABAA a5 receptor inverse agonist, RO4938581 in rats and monkeys. Materials and methods: The in vitro profile was determined using radioligand binding and electrophysiological assays for the GABAA a1, a2, a3, and a5 receptors. Long-term potentiation (LTP) was performed in mouse hippocampal slices. Cognitive effects were assessed in rats in the delayed match to position (DMTP) task and the Morris water maze. In monkeys, the object retrieval task was used. Pro-convulsant and anxiogenic potentials were evaluated in mice and rats. In vivo receptor occupancy was determined using [3H]-RO0154513. Results: RO4938581 is a potent inverse agonist at the GABAA a5 receptor, with both binding and functional selectivity, enhancing hippocampal LTP. RO4938581 reversed scopolamine-induced working memory impairment in the DMTP task (0.3-1 mg/kg p.o.) and diazepam-induced spatial learning impairment (1-10 mg/kg p.o.). RO4938581 improved executive function in monkeys (3-10 mg/kg p.o.). Importantly, RO4938581 showed no anxiogenic and pro-convulsive potential. RO4938581 dose-dependently bound to GABAA a5 receptors and approximately 30% receptor occupancy was sufficient to produce enhanced cognition in the rat. Conclusions: The data further support the potential of GABAA a5 receptors as a target for cognition-enhancing drugs. The dual binding and functional selectivity offers an ideal profile for cognition-enhancing effects without the unwanted side effects associated with activity at other GABAA receptor subtypes.