Antagonism of AMPA receptors produces anxiolytic-like behavior in rodents: Effects of GYKI 52466 and its novel analogues |
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Authors: | Gábor L Kapus István Gacsályi Miklos Vegh Hajnalka Kompagne Endre Heged?s Csilla Leveleki László G Hársing József Barkóczy András Bilkei-Gorzó György Lévay |
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Institution: | (1) Division of Preclinical Research, EGIS Pharmaceuticals Plc., 10. P.O. Box 100, H-1475 Budapest, Hungary;(2) Chemical Research Division, EGIS Pharmaceuticals Plc., Budapest, Hungary;(3) College of Healthcare, Semmelweis University, Budapest, Hungary |
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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. |
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Keywords: | Anxiolytic AMPA antagonist Glutamate GYKI 52466 EGIS-8332 EGIS-10608 Light– dark Plus-maze Vogel conflict |
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