Behavioural pharmacology of the α5-GABA A receptor antagonist S44819: Enhancement and remediation of cognitive performance in preclinical models

Abstract

Previous work has shown that S44819 is a novel GABAA receptor (GABAR) antagonist, which is selective for extrasynaptic GABARs incorporating the α5 subunit (α5-GABARs). The present study reports on the preclinical neuropsychopharmacological profile of S44819. Significantly, no sedative or pro-convulsive side effects of S44819 were found at doses up to 30 mg/kg i.p. Object recognition (OR) memory in intact mice was enhanced by S44819 (0.3 mg/kg p.o.) given before the acquisition trial. Mice treated with phencyclidine for two weeks and tested six days after the cessation of treatment failed to show OR memory. This deficit was corrected by a single administration of S44819 (0.1, 0.3 or 1 mg/kg p.o.) prior to the acquisition trial. The amnestic effect of ketamine in rats tested in the eight-arm radial maze (reference and working memory versions) was blocked by S44819 (3 mg/kg p.o.). Extinction of cued fear was preserved during treatment with S44819 (3 mg/kg/diem i.p.). Administration of S44819 had no significant effect in the Vogel-conflict test, the elevated plus maze, the forced swim, the marble-burying and the tail-suspension tests. In contrast, anxiolytic/antidepressant-like effects of the compound were found in paradigms that have mnemonic components, such as social interaction, fear-potentiated startle and social avoidance induced by negative life experience. In summary, S44819 enhanced intact recognition memory and ameliorated memory deficits induced by inhibition of NMDA receptors. Anxiolytic/antidepressant efficacy was limited to paradigms involving cognitive function. In conclusion, S44819 is a novel psychoactive pro-cognitive compound with potential as a therapeutic agent in dementia.

Selective inhibition of extra-synaptic α5-GABA A receptors by S44819, a new therapeutic agent

“…A likely mechanism underlying this effect of S44819 is the lowering of the firing threshold of CA1 principal neurons, thereby enabling cholinergic triggering of hippocampal network oscillations (Cobb and Davies, 2005;Fisahn et al, 1998;Huerta and Lisman, 1995) in the face of inhibition by scopolamine. We have now reported a further characterisation of the behavioural actions of S44819 in preclinical models (Gacsályi et al, 2017). Consistent with these behavioural investigations, pharmacokinetic studies in rodents reveal S44819 to achieve active brain concentrations (brain:plasma ratio of 1:2 for male mice and 1:4 for male rats), with an appropriate time course (Gacsályi et al, 2017).…”

“…However, in contrast, relatively high concentrations of S44819 (10 µM) did not inhibit synaptic GABA A Rs and did not produce repetitive firing. Indeed, in mice behaviourallyactive doses of S44819 are not pro-convulsant, nor do they reduce the dose of pentylenetetrazol required to induce convulsions (Gacsályi et al, 2017). Selective α5-GABA A R NAMs facilitate hippocampal LTP (Atack, 2011).…”

“…We have now reported a further characterisation of the behavioural actions of S44819 in preclinical models (Gacsályi et al, 2017). Consistent with these behavioural investigations, pharmacokinetic studies in rodents reveal S44819 to achieve active brain concentrations (brain:plasma ratio of 1:2 for male mice and 1:4 for male rats), with an appropriate time course (Gacsályi et al, 2017). Importantly In conclusion, S44819 is a selective, competitive, inhibitor of extra-synaptic α5-GABA A Rs and provides a new mechanistic tool to elucidate the role of α5-GABA A Rs in neuronal signaling and behavior.…”

Postacute Delivery of GABA A α5 Antagonist Promotes Postischemic Neurological Recovery and Peri-infarct Brain Remodeling

“… 5 In rats and mice, S44819 improved memory and reduced anxiety in a variety of cognitive tests, when administered orally at doses between 0.3 and 10 mg/kg body weight. 6 …”

Antagonists of Ionotropic Receptors for the Inhibitory Neurotransmitter GABA: Therapeutic Indications

“…Thus, S44819 is a competitive antagonist, unlike other α5-subunit selective drugs that act as negative allosteric modulators by binding to the benzodiazepine recognition site between at the α5-γ2 subunits [71,72]. Agents that are selective for α5 subunit-containing GABA A receptors enhance cognitive performance in a variety of animal models without sedative or pro-convulsive efects [73]. SR44819 has been shown in healthy young humans to be orally active, reaching the cerebral cortex on oral administration where it increases cortical excitability [74], acting on extrasynaptic receptors to reduce tonic inhibition.…”