Involvement of cholinergic and GABAergic systems in the reversal of memorydisruption by NS-105, a cognition enhancer

The effects of (+)-5-oxo-D-prolinepiperidinamide monohydrate (NS-105) on th e scopolamine-, electrolytic lesion of the nucleus basalis magnocellularis (NBM)-, AF64A-, baclofen-, cerebral ischemia- and electroconvulsive shock ( ECS)-induced memory disruption in the passive avoidance response or radial arm maze tasks were investigated in rats. The effects of NS-105 were compar ed with those of aniracetam, bifemelane, idebenone, and indeloxazine in two tasks of the passive avoidance response. Furthermore, effects of NS-105 on in vivo release of acetylcholine (ACh) in the cerebral cortex, high-affini ty choline uptake (HACU) of the cerebral cortex in rats with lesion of NBM, HACU of the hippocampus in rats treated with pentobarbital and activity of choline acetyltransferase (ChAT) of the cerebral cortex in rats with lesio n of NBM were examined. NS-105 showed antiamnestic actions in a variety of animal models of cholinergic dysfunction employed in this study. Aniracctam improved memory disruption caused by scopolamine, but bifemelane, idebenon e, and indeloxazine did not. NS-105 (10 mg/kg) showed the increase of ACh r elease from the cerebral cortex and the enhancement of HACU both in the cer ebral cortex and hippocampus, but showed no change in activity of ChAT. NS- 105 also reversed memory disruption induced by baclofen, a potent GABA, rec eptor agonist, but all of reference drugs did not. These results suggest th at antiamnestic action of NS-105 is due to the facilitation of cholinergic neuronal activity and the suppression of GABAB receptor-mediated responses. (C) 1999 Elsevier Science Inc.