Antagonism of AMPA receptors produces anxiolytic-like behavior in rodents: effects of GYKI 52466 and its novel analogues.
Psychopharmacology (Berl)
; 198(2): 231-41, 2008 Jun.
Article
in En
| MEDLINE
| ID: mdl-18363046
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 ANDMETHODS:
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Anti-Anxiety Agents
/
Benzodiazepines
/
Receptors, AMPA
/
Excitatory Amino Acid Antagonists
Limits:
Animals
Language:
En
Journal:
Psychopharmacology (Berl)
Year:
2008
Type:
Article
Affiliation country:
Hungary