摘要：

Several neuropeptides have recently been found to be involved in motivational, memory, and learning processes. Therefore, we tested the hypothesis that the peptidase (EC 3.4.15.1) inhibitor Hoe 288 modulated cognitive functions. Hoe 288 exhibited nootropic effects in uphill avoidance in mice (30 mg/kg orally administered [p.o.]). Scopolamineinduced amnesia in mice and rats was antagonized after subchronic administration for two or three days (1-10 mg/kg p.o. or intraperitoneally [i.p.]) in step-through avoidance and an eight-arm-radial maze, respectively. The resulting bell-shaped dose-response curves had a maximum effect at 3 mg/kg. To elucidate the underlying neurochemical effects, ex vivo experiments in rats were performed: acute or repeated administration of Hoe 288 (0.03 - 3 mg/kg i.p.) induced a significant decrease of acetylcholine (ACh) content in certain brain areas that lasted up to 6 hr after treatment. The reduced brain ACh content was most likely due to an enhanced ACh release, as coadministration of the choline uptake inhibitor hemicholinium-3 (HC-3) and Hoe 288 potentiated the decrease of ACh induced by HC-3. Choline acetyltransferase activity in brain increased after acute and subchronic administration of the peptidase inhibitor. Receptor-mediated effects of ACh were estimated indirectly by its stimulation of guanylate cyclase. Hoe 288 increased cGMP content in a comparable dose range (0.3 - 1 mg/kg i.p.). The converting enzyme inhibitor Hoe 288 was shown to influence acquisition and retention of information in rodents, and the effects on ACh metabolism are in concordance with results obtained with potential nootropics in animal experiments.

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