ANXIOLYTIC-LIKE EFFECTS OF THE NOVEL CHOLINERGIC CHANNEL ACTIVATOR ABT-418

The hydrochloride salt of (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl) iso xazole (ABT-418), a potent activator of select subtypes of neuronal ni cotinic acetylcholine receptors enhanced retention in memory tests and induced anxiolytic-like effects in mice in the elevated plus maze. In the present studies in rat, ABT-418 induced a significant increase in the time spent by the rats in the open arms of the elevated plus maze (0.62 mu mol/kg i.p.); the effect persisted up to 60 min after the in jection and was blocked by mecamylamine (15 mu mol/kg), a centrally ac ting nicotinic acetylcholine receptor channel blocker. ABT-418 was and fold and 1.6-fold more potent than diazepam and ondansetron, respecti vely. The anxiolytic-like effect of ABT-418 was observed after oral ad ministration in rats (10-30 mu mol/kg) and at slightly higher doses in 20-month-old rats (1.9 mu mol/kg i.p.). Major metabolites of ABT-418 -methyl-5-(3-methyl-5-isoxazolyl)-2-pyrrolidinone, cis-ABT-418 N-oxide and trans-ABT-418 N-oxide] were inactive in the plus maze in mice up to 6.2 mu mol/kg, did not affect body temperature and had minimal effe cts on locomotion. Like (-)-nicotine, ABT-418 was effective (4 and 13 mu mol kg(-1) day(-1)) to induce anxiolytic-like effects after a 14-da y treatment through minipumps implanted subcutaneously. Acute administ ration of ABT-418 (0.62 mu mol/kg i.p.) also attenuated the anxiogenic -like effect elicited by withdrawal from chronic (-)-nicotine treatmen t. ABT-418 (0.62 and 1.9 mu mol/kg i.p.) did not impair spatial memory in the water maze and did not potentiate the amnestic effects of diaz epam (7.0 mu mol/kg i.p.) in this test. These data demonstrate that AB T-418 exhibits anxiolytic-like properties in rodents independently of the route of administration of the compound and that it may represent a novel therapeutic approach for the treatment of emotional disorders that have anxiety as a major behavioral manifestation.