ABT-089 [2-METHYL-3(2-(S)-PYRROLIDINYLMETHOXY)PYRIDINE DIHYDROCHLORIDE] .2. A NOVEL CHOLINERGIC CHANNEL MODULATOR WITH EFFECTS ON COGNITIVEPERFORMANCE IN RATS AND MONKEYS

ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochlorid e], a novel ligand at neuronal nicotinic acetylcholine receptors with reduced adverse effects and improved oral bioavailability relative to (-)-nicotine, was tested in a variety of cognitive tests in rats and m onkeys. Administered acutely, ABT-089 only marginally improved the spa tial discrimination water maze performance of septal-lesioned rats. Ho wever, more robust improvement (45% error reduction on the last traini ng day) was observed when ABT-089 was administered continuously via su bcutaneous osmotic pumps (minimum effective dose: 1.3 mu mol/kg/day). Continuous infusion of (-)nicotine produced comparable improvement in the spatial discrimination water maze performance of septal-lesioned r ats, but a 40-fold higher dose of (-)-nicotine was required (62 mu mol /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 dis crimination water maze. The compound induced a small impairment in you ng rats on the standard water maze, but not on the two-platform task. A probe trial conducted after additional training in the standard wate r maze revealed no age or drug effects. ABT-089 did not affect perform ance of either the aged or young rats during inhibitory (passive) avoi dance training. Also, continuous infusion of ABT-089 did not affect re sponses to acoustic startle or prepulse inhibition of acoustic startle in young, aged or septal-lesioned rats and did not affect locomotor a ctivity in either sham-lesioned or septal-lesioned rats. In monkeys, a cute administration of ABT-089 modestly improved the delayed matching- to-sample performance of mature, adult monkeys and more robustly impro ved performance in aged monkeys. Improved performance in the aged monk eys was restricted to the longest delay intervals and was not accompan ied by changes in response latencies.