RO4938581, a novel cognitive enhancer acting at GABAA alpha5 subunit-containing receptors

Psychopharmacology (Berl). 2009 Jan;202(1-3):207-23. doi: 10.1007/s00213-008-1357-7. Epub 2008 Oct 21.


Rationale: GABAA alpha5 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 alpha5 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 alpha1, alpha2, alpha3, and alpha5 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 alpha5 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 alpha5 receptors and approximately 30% receptor occupancy was sufficient to produce enhanced cognition in the rat.

Conclusions: The data further support the potential of GABAA alpha5 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.

MeSH terms

  • Animals
  • Benzodiazepines / pharmacology*
  • Cell Line
  • Cognition / drug effects*
  • Dose-Response Relationship, Drug
  • Female
  • Haplorhini
  • Hippocampus / drug effects
  • Imidazoles / pharmacology*
  • In Vitro Techniques
  • Learning / drug effects
  • Long-Term Potentiation / drug effects
  • Male
  • Membranes / drug effects
  • Memory / drug effects
  • Mice
  • Mice, Inbred DBA
  • Motor Activity / drug effects
  • Nootropic Agents / pharmacology*
  • Patch-Clamp Techniques
  • Plasmids
  • Rats
  • Rats, Wistar
  • Receptors, GABA-A / drug effects*
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism
  • Recombinant Proteins
  • Seizures / chemically induced


  • 3-bromo-10-difluoromethyl-9H-imidazo(1,5-a)(1,2,4)triazolo(1,5-d)(1,4)benzodiazepine
  • Gabra5 protein, rat
  • Imidazoles
  • Nootropic Agents
  • Receptors, GABA-A
  • Recombinant Proteins
  • Benzodiazepines