Anxiolytic effects of aniracetam in three different mouse models of anxiety and the underlying mechanism.
The anxiolytic effects of aniracetam have not been proven in animals despite its clinical usefulness for post-stroke anxiety. This study, therefore, aimed to characterize the anxiolytic effects of aniracetam in different anxiety models using mice and to examine the mode of action. In a social interaction test in which all classes (serotonergic, cholinergic and dopaminergic) of compounds were effective, aniracetam (10-100 mg/kg) increased total social interaction scores (time and frequency), and the increase in the total social interaction time mainly reflected an increase in trunk sniffing and following. The anxiolytic effects were completely blocked by haloperidol and nearly completely by mecamylamine or ketanserin, suggesting an involvement of nicotinic acetylcholine, 5-HT2A and dopamine D2 receptors in the anxiolytic mechanism. Aniracetam also showed anti-anxiety effects in two other anxiety models (elevated plus-maze and conditioned fear stress tests), whereas diazepam as a positive control was anxiolytic only in the elevated plus-maze and social interaction tests. The anxiolytic effects of aniracetam in each model were mimicked by different metabolites (i.e., p-anisic acid in the elevated plus-maze test) or specific combinations of metabolites. These results indicate that aniracetam possesses a wide range of anxiolytic properties, which may be mediated by an interaction between cholinergic, dopaminergic and serotonergic systems. Thus, our findings suggest the potential usefulness of aniracetam against various types of anxiety-related disorders and social failure/impairments.
Nakamura
K
K
CNS Supporting Laboratory, Nippon Roche Research Center, 200 Kajiwara, Kamakura, 247-8530, Kanagawa, Japan. kazuo.nakmura@roche.com
Kurasawa
M
M
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects; D001971:Bromocriptine / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005239:Fear / Q000523:psychology; D016666:Fluvoxamine / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D007215:Indophenol / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D020912:Moclobemide / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009661:Nortriptyline / Q000494:pharmacology; D010830:Physostigmine / Q000494:pharmacology; D010848:Picolinic Acids / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D012919:Social Behavior; D013315:Stress, Psychological / Q000503:physiopathology / Q000517:prevention & control / Q000523:psychology
D014151:Anti-Anxiety Agents; D018492:Dopamine Antagonists; D018733:Nicotinic Antagonists; D010848:Picolinic Acids; D011760:Pyrrolidinones; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C113896:dimethoxy-4-indophenyl-2-aminopropane; D001971:Bromocriptine; C059303:lazabemide; D007215:Indophenol; C036466:aniracetam; D008464:Mecamylamine; D009538:Nicotine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D010830:Physostigmine; D009661:Nortriptyline; D006220:Haloperidol; D016666:Fluvoxamine; D020912:Moclobemide; D003975:Diazepam