Antidepressant-like effects of aniracetam in aged rats and its mode of action

Rationale: Aniracetam has been reported to be efficacious for treating poststroke depression, but no studies that basically examined the antidepressive effects have been made. Objective: We aimed to test the antidepressant-like property of aniracetam in rats and to clarify the mechanisms of action through the interaction studies with some receptor antagonists. Methods: Antidepressant-like effects of aniracetam and various classes of compounds including different antidepressants were examined in a forced swim test with young (9 weeks old) and aged (25-30 months old) rats. Rats were exposed to a 5-min swim in a test session on day 2 following a 15-min swim in a training session on day 1, and immobility time during the period on day 2 was measured. The test compounds were administered subacutely (three doses over 2 days) or acutely (0.5 h before the testing). Results: Standard antidepressants except for tandospirone significantly reduced immobility time in both young and aged rats. Aniracetam (10-100 mg/kg PO) failed to decrease immobility time in young rats, but it (100 mg/kg PO) significantly shortened immobility in aged rats, the effects of which were mainly mimicked by combined treatment of the metabolites, 2-pyrrolidinone and N-anisoyl-GABA. The effects of aniracetam was reversed completely by mecamylamine (10 mg/kg IP) or haloperidol (0.1 mg/kg IP) and slightly by ketanserin (1 m/kg IP) but was potentiated by scopolamine (0.03 mg/kg IP). Conclusions: These results indicate that aniracetam acts more effective when the forced swim stress-induced immobility is accompanied with brain dysfunction that occurs with aging. The antidepressant-like activity of aniracetam, which is probably due to the combined effects of 2-pyrrolidinone and N-anisoyl-GABA, may be mediated by mainly facilitating dopaminergic transmission (dopamine release and dopamine D-2 receptor activation) through nicotinic acetylcholine receptor stimulation.