PT - JOURNAL ARTICLE AU - J D Brioni AU - A B O'Neill AU - D J Kim AU - M J Buckley AU - M W Decker AU - S P Arneric TI - Anxiolytic-like effects of the novel cholinergic channel activator ABT-418. DP - 1994 Oct 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 353--361 VI - 271 IP - 1 4099 - http://jpet.aspetjournals.org/content/271/1/353.short 4100 - http://jpet.aspetjournals.org/content/271/1/353.full SO - J Pharmacol Exp Ther1994 Oct 01; 271 AB - 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 mumol/kg i.p.); the effect persisted up to 60 min after the injection and was blocked by mecamylamine (15 mumol/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 was observed after oral administration in rats (10-30 mumol/kg) and at slightly higher doses in 20-month-old rats (1.9 mumol/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 mumol/kg, did not affect body temperature and had minimal effects on locomotion. Like (-)-nicotine, ABT-418 was effective (4 and 13 mumol 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 mumol/kg i.p.) also attenuated the anxiogenic-like effect elicited by withdrawal from chronic (-)-nicotine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)