Anxiolytic-like effects of the novel cholinergic channel activator ABT-418
Brioni, J.D.; O'Neill, A.B.; Kim, D.J.; Buckley, M.J.; Decker, M.W.; Arneric, S.P.
Journal of Pharmacology and Experimental Therapeutics 271(1): 353-361
1994
ISSN/ISBN: 0022-3565 PMID: 7965735 Document Number: 432913
The hydrochloride salt of (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl) isoxazole (ABT-418), a potent activator of select subtypes of neuronal nicotinic acetylcholine receptors enhanced retention in memory tests and induced anxiolytic-like effects in mice in the elevated plus maze. In the present studies in rats, 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 injection and was blocked by mecamylamine (15 mu-mol/kg), a centrally acting nicotinic acetylcholine receptor channel blocker. ABT-418 was 6-fold and 1.6-fold more potent than diazepam and ondansetron, respectively. The anxiolytic-like effect of ABT-418 wa observed after oral administration 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 ((S)-1-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 effects 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-day treatment through minipumps implanted subcutaneously. Acute administration of ABT-418 (0.62 mu-mol/kg i.p.) also attenuated the anxiogenic-like effect elicited by withdrawal from chronic (-)-nicotine treatment. 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 diazepam (7.0 mu-mol/kg i.p.) in this test. These data demonstrate that ABT-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.