Antagonism of AMPA receptors produces anxiolytic-like behavior in rodents: Effects of GYKI 52466 and its novel analogues

Gábor L. Kapus, István Gacsályi, Miklos Vegh, Hajnalka Kompagne, Endre Hegedűs, Csilla Leveleki, László G. Hársing, József Barkóczy, András Bilkei-Gorzó, György Lévay

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27 Citations (Scopus)

Abstract

Rationale: Although emerging number of data supports the role of glutamate receptors and the potential of their antagonists in anxiety disorders, the involvement of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors in anxiety is less well characterized. Objective: To evaluate the anxiolytic potential of 2,3-benzodiazepine (2,3BDZ) type AMPA receptor antagonists in various models of anxiety. Materials and methods: Whole-cell currents, hippocampal field potentials, elevated plus maze (EPM), meta-chlorophenylpiperazine (mCPP)-induced anxiety model, Vogel test in rats and light-dark test (LD) in mice were used to determine AMPA/kainite receptor properties and anxiolytic-like activity of a series of 2,3BDZ-type compounds. Results: The reference compound GYKI 52466 was proved active in two anxiety models in non-sedative doses: minimal effective dose (MED) was especially low in EPM (0.01 mg/kg) GYKI 53405 and GYKI 53655 showed anxiolytic-like activity in two tests (EPM and mCPP). EGIS-8332 was active in EPM and LD while EGIS-9637 showed anxiolytic-like potency in EPM, mCPP and Vogel model. EGIS-10608 was the most effective compound among 2,3BDZs tested in EPM and Vogel models (MEDs are 0.01 and 2.5 mg/kg, respectively). 2,3BDZs were active in anxiety models at doses lower than those produced sedative effects. NBQX showed anxiolytic-like activity in EPM only (3 mg/kg). Conclusions: The results show that non-competitive AMPA receptor antagonists can profoundly block anxiety-like behavior in rodents independently from their motor depressant activity. However, the sedative properties at higher doses might limit their therapeutic utility as new anxiolytic drugs.

Original languageEnglish
Pages (from-to)231-241
Number of pages11
JournalPsychopharmacology
Volume198
Issue number2
DOIs
Publication statusPublished - Jun 2008

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Keywords

  • AMPA antagonist
  • Anxiolytic
  • EGIS-10608
  • EGIS-8332
  • GYKI 52466
  • Glutamate
  • Light-dark
  • Plus-maze
  • Vogel conflict

ASJC Scopus subject areas

  • Pharmacology

Cite this

Kapus, G. L., Gacsályi, I., Vegh, M., Kompagne, H., Hegedűs, E., Leveleki, C., Hársing, L. G., Barkóczy, J., Bilkei-Gorzó, A., & Lévay, G. (2008). Antagonism of AMPA receptors produces anxiolytic-like behavior in rodents: Effects of GYKI 52466 and its novel analogues. Psychopharmacology, 198(2), 231-241. https://doi.org/10.1007/s00213-008-1121-z