Anxiolytic-like effects of the novel cholinergic channel activator ABT-418.
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)
Brioni
J D
JD
(D47W) Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois.
O'Neill
A B
AB
Kim
D J
DJ
Buckley
M J
MJ
Decker
M W
MW
Arneric
S P
SP
D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D003072:Cognition Disorders / Q000139:chemically induced; D003975:Diazepam / Q000494:pharmacology; D007555:Isoxazoles / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D009538:Nicotine / Q000494:pharmacology; D011759:Pyrrolidines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome
D014151:Anti-Anxiety Agents; D007555:Isoxazoles; D011759:Pyrrolidines; C088383:3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole; D008464:Mecamylamine; D009538:Nicotine; D003975:Diazepam