With passive avoidance (PA), Morris water maze (WM) and eight-arm radial maze tasks, we evaluated the memory-enhancing action of
FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a compound which we have found through rational
drug screening based on our hypothesis that penile erection is a valid predictor of central
cholinergic activation. Memory performance in the tasks was impaired in aged (24- to 26-months-old) rats as well as in rats with nucleus basalis magnocellularis lesions.
Scopolamine (1 mg/kg i.p.) treatment induced memory impairment in PA and WM; treatment with
cysteamine (200 mg/kg s.c.) induced memory impairment in PA but not in WM, whereas fimbria fornix lesioning affected the rats in the opposite manner.
FK960 (0.1-10 mg/kg i.p.) ameliorated all the memory impairments except those induced by
cysteamine or fimbria fornix lesion, and the dose-response curves were bell shaped with maximal response at 1 to 3.2 mg/kg. The effects of
FK960 on the
scopolamine-induced memory impairment in the PA and/or WM were abolished by
cysteamine (200 mg/kg s.c.), dl-
p-chlorophenylalanine methyl ester hydrochloride (150 mg/kg i.p. for 3 days) or raphe lesioning, but not by neonatal
6-hydroxydopamine (35 micrograms/head) treatment. Neurochemical analysis revealed that
cysteamine and raphe lesions reduced brain
somatostatin and
serotonin contents, respectively. The treatment with
FK960 (0.32-320 mg/kg p.o.) dose-dependently increased both
serotonin and 5-hydroxyindoleacetic
acid levels in the brain areas examined and significantly increased hippocampal
somatostatin contents at the smaller doses. From these results, we conclude that
FK960 ameliorates
cognitive dysfunction through an activation of the somatostatinergic-serotonergic link.