Behavioural pharmacology of the α5-GABAA receptor antagonist S44819

Enhancement and remediation of cognitive performance in preclinical models

István Gacsályi, Krisztina Móricz, Gábor Gigler, János Wellmann, Katalin Nagy, István Ling, József Barkóczy, József Haller, Jeremy J. Lambert, G. Szénási, Michael Spedding, Ferenc A. Antoni

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Previous work has shown that S44819 is a novel GABAA receptor (GABAAR) antagonist, which is selective for extrasynaptic GABAARs incorporating the α5 subunit (α5-GABAARs). 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.

Original languageEnglish
Pages (from-to)30-38
Number of pages9
JournalNeuropharmacology
Volume125
DOIs
Publication statusPublished - Oct 1 2017

Fingerprint

GABA-A Receptor Antagonists
Pharmacology
Anti-Anxiety Agents
Antidepressive Agents
Fear
Hindlimb Suspension
Phencyclidine
Withholding Treatment
Calcium Carbonate
Life Change Events
Memory Disorders
Ketamine
Interpersonal Relations
N-Methyl-D-Aspartate Receptors
Hypnotics and Sedatives
Short-Term Memory
Cognition
Dementia
Cognitive Remediation
Therapeutics

Keywords

  • Alpha5-GABA antagonists
  • Behavioural pharmacology
  • Cognitive performance
  • GABA receptors
  • S44819

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

Behavioural pharmacology of the α5-GABAA receptor antagonist S44819 : Enhancement and remediation of cognitive performance in preclinical models. / Gacsályi, István; Móricz, Krisztina; Gigler, Gábor; Wellmann, János; Nagy, Katalin; Ling, István; Barkóczy, József; Haller, József; Lambert, Jeremy J.; Szénási, G.; Spedding, Michael; Antoni, Ferenc A.

In: Neuropharmacology, Vol. 125, 01.10.2017, p. 30-38.

Research output: Contribution to journalArticle

Gacsályi, I, Móricz, K, Gigler, G, Wellmann, J, Nagy, K, Ling, I, Barkóczy, J, Haller, J, Lambert, JJ, Szénási, G, Spedding, M & Antoni, FA 2017, 'Behavioural pharmacology of the α5-GABAA receptor antagonist S44819: Enhancement and remediation of cognitive performance in preclinical models', Neuropharmacology, vol. 125, pp. 30-38. https://doi.org/10.1016/j.neuropharm.2017.07.005
Gacsályi, István ; Móricz, Krisztina ; Gigler, Gábor ; Wellmann, János ; Nagy, Katalin ; Ling, István ; Barkóczy, József ; Haller, József ; Lambert, Jeremy J. ; Szénási, G. ; Spedding, Michael ; Antoni, Ferenc A. / Behavioural pharmacology of the α5-GABAA receptor antagonist S44819 : Enhancement and remediation of cognitive performance in preclinical models. In: Neuropharmacology. 2017 ; Vol. 125. pp. 30-38.
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