Our previous studies have demonstrated that
FK960 (FR59960; N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate), a novel antidementia
piperazine derivative, exerts beneficial effects on
memory deficits in various animal models of
amnesia in rats [M. Yamazaki, N. Matsuoka, N. Maeda, Y. Ohkubo, I. Yamaguchi,
FK960 N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate ameliorates the
memory deficits in rats through a novel mechanism of action, J. Pharmacol. Exp. Ther., 279 (1996) 1157-1173.] and in rhesus monkeys [N. Matsuoka, T.G. Aigner,
FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel potential antidementia
drug, improves visual recognition memory in rhesus monkeys: comparison with
physostigmine, J. Pharmacol. Exp. Ther., 280 (1997) 1201-1209]. To clarify the synaptic mechanisms of its antiamnesic action,
FK960 was investigated for its effects on the development of long-term potentiation (LTP) in guinea-pig hippocampal slices. The magnitude of LTP of population spike recorded in CA3 pyramidal neurons was significantly augmented by perfusing
FK960 (10-9-10-6 M) for 25 min before and during tetanic stimulation of the mossy fibers, whereas the basal amplitude of population spikes before
tetanus was hardly affected by the
drug. The dose-response curve was bell-shaped with a maximal augmentation
at 10-7 M.
Scopolamine (10-6 M) per se had little effect on the magnitude of LTP in the mossy fiber-CA3 pathway, but significantly attenuated its enhancement by
FK960 (10-7 M). In hippocampal slices from animals treated with
cysteamine (200 mg/kg, s.c.), which was shown to deplete the hippocampal
somatostatin,
FK960 (10-7 M) hardly affected the LTP. These results suggest that
FK960 enhances the magnitude of LTP in the mossy fiber-CA3 pathway through an activation of the
cholinergic-somatostatinergic link in the hippocampal formation. Furthermore, it can be postulated that the
drug regulates the cognitive function by modulating directly synaptic plasticity in the hippocampal neuronal network.