The anxiolytic effect of perampanel and possible mechanisms mediating its anxiolytic effect in mice

The aim of this study is to investigate the anxiolytic activity of perampanel, a non-competitive antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors, which is approved for partial-onset seizures in patients with epilepsy, and its mechanism of action.

The anxiolytic activity of perampanel at the doses of 0.25, 0.5, 1, 2, and 4 mg/kg intraperitoneally (i.p.) was investigated in mice using elevated plus-maze, hole-board, and open-field tests. The findings were compared to the anxiolytic activity of gamma-aminobutyric acid type A benzodiazepine (GABA_A/BZ) receptor allosteric modulator diazepam (1 mg/kg, i.p.) and AMPA antagonist GYKI-53655 (5 mg/kg, i.p.). The mechanisms of action of perampanel were evaluated by pre-treatment with GABA_A/BZ receptor antagonist flumazenil (3 mg/kg, i.p.), serotonin 5-hydroxytryptamine 1A (5-HT_1A) antagonist WAY-100635 (1 mg/kg, i.p.), and α₂-adrenoreceptor antagonist yohimbine (5 mg/kg, i.p.).

In the elevated plus-maze and open-field tests, perampanel at the dose of 0.5 mg/kg, and in the hole-board test, at the doses of 0.25, 0.5, and 1 mg/kg demonstrated an anxiolytic effect without altering the locomotor activity. The effect of perampanel was comparable to the effect of diazepam. Stimulation of GABA_A/BZ and α₂-adrenergic receptors contributed to the anxiolytic effect of perampanel, since significant antagonisms were determined in various behavioral parameters by the antagonist pre-treatments.

AMPA antagonism is believed to provide the determined anxiolytic activity of perampanel. Increased GABAergic tonus induced by AMPA receptor antagonism along with other systems, especially the noradrenergic system, might be involved in the anxiolytic activity.