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ABT-089 [2-Methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride]: II. A Novel Cholinergic Channel Modulator with Effects on Cognitive Performance in Rats and Monkeys
ABT-089 [2-methyl-3-(2-( S )-pyrrolidinylmethoxy)pyridine dihydrochloride], a novel ligand at neuronal nicotinic acetylcholine receptors with reduced adverse effects and improved oral bioavailability relative to (â)-nicotine, was tested in a variety of cognitive tests in rats and monkeys. Administ...
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Published in: | The Journal of pharmacology and experimental therapeutics 1997-10, Vol.283 (1), p.247-258 |
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Main Authors: | , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Online Access: | Get full text |
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Summary: | ABT-089 [2-methyl-3-(2-( S )-pyrrolidinylmethoxy)pyridine dihydrochloride], a novel ligand at neuronal nicotinic acetylcholine receptors with reduced
adverse effects and improved oral bioavailability relative to (â)-nicotine, was tested in a variety of cognitive tests in
rats and monkeys. Administered acutely, ABT-089 only marginally improved the spatial discrimination water maze performance
of septal-lesioned rats. However, more robust improvement (45% error reduction on the last training day) was observed when
ABT-089 was administered continuously via subcutaneous osmotic pumps (minimum effective dose: 1.3 μmol/kg/day). Continuous infusion of (â)-nicotine produced comparable
improvement in the spatial discrimination water maze performance of septal-lesioned rats, but a 40-fold higher dose of (â)-nicotine
was required (62 μmol/kg/day). Continuous infusion of ABT-089 to aged rats enhanced spatial learning in a standard Morris
water maze, as indexed by spatial bias exhibited during a probe trial conducted after 4 days of training, but not when they
were subsequently trained in a two-platform spatial discrimination water maze. The compound induced a small impairment in
young rats on the standard water maze, but not on the two-platform task. A probe trial conducted after additional training
in the standard water maze revealed no age or drug effects. ABT-089 did not affect performance of either the aged or young
rats during inhibitory (passive) avoidance training. Also, continuous infusion of ABT-089 did not affect responses to acoustic
startle or prepulse inhibition of acoustic startle in young, aged or septal-lesioned rats and did not affect locomotor activity
in either sham-lesioned or septal-lesioned rats. In monkeys, acute administration of ABT-089 modestly improved the delayed
matching-to-sample performance of mature, adult monkeys and more robustly improved performance in aged monkeys. Improved performance
in the aged monkeys was restricted to the longest delay intervals and was not accompanied by changes in response latencies. |
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ISSN: | 0022-3565 1521-0103 |