Antidepressant-like effects of aniracetam in aged rats and its mode of action.
BACKGROUND
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 D2 receptor activation) through nicotinic acetylcholine receptor stimulation.
Nakamura
K
K
CNS Supporting Laboratory, Nippon Roche Research Center, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan. kazuo.nakamura@roche.com
Tanaka
Y
Y
D000284:Administration, Oral; D000375:Aging / Q000502:physiology*; D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D003863:Depression / Q000188:drug therapy; D004359:Drug Therapy, Combination; D007103:Immobilization; D007274:Injections, Intraperitoneal; D008297:Male; D018697:Nootropic Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D011760:Pyrrolidinones / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013312:Stress, Physiological / Q000188:drug therapy; D013550:Swimming / Q000502:physiology
D000928:Antidepressive Agents; D018697:Nootropic Agents; D011760:Pyrrolidinones; C036466:aniracetam