Antagonism of AMPA receptors produces anxiolytic-like behavior in rodents: Effects of GYKI 52466 and its novel analogues
The activity of anxiolytic and other drugs in a light-dark test situation was studied in rats treated with the anxiogenic compound m-chlorophenyl-piperazine (mCPP). mCPP 0.5 mg/kg significantly diminished the exploratory activity of the animals in the light compartment of the apparatus. Drugs to be tested against mCPP-induced anxiety when studied alone (not in combination with mCPP) did not significantly alter the activity of rats in the light-dark apparatus, except yohimbine, which reduced the movement time values in the lit area. 1,4-Benzodiazepines [diazepam (0.1–4 mg/kg) and chlordiazepoxide (2–8 mg/kg)], 5-HT2A/2C antagonists [ritanserin (0.25–8 mg/kg) and deramciclane (0.5–8 g/kg)], the 5-HT3 antagonist MDL-72222 (3 mg/kg) and ethanol (2–4 mg/kg) significantly reduced the effect of mCPP. A dose-dependent increase in the exploratory activity of mCPP-treated animals was found in the 2,3-benzodiazepine girisopam (2.5–5 mg/kg)-treated groups. Tofisopam, another 2,3-benzodiazepine molecule, also showed activity against mCPP, although its effect was not statistically significant. The 5-HT1A partial agonist buspirone was also active in the dose range of 0.25–0.5 mg/kg, while the 5-HT1A full agonist 8-OH-DPAT was the only drug with presumed anxiolytic activity that clearly lacked any effect in this model. Imipramine, amitriptyline, morphine, naloxone, haloperidol, clozapine, amphetamine, yohimbine, carbamazepine and diphenylhydantoin were not effective. We conclude that mCPP-induced anxiety in the light-dark box is a potent and useful method for screening and detecting anxiolytic activity of a wide range of compounds with various modes of action.