We have demonstrated that FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel putative anti-dementia drug of piperazine derivative, ameliorates memory deficits in a variety of animal models of dementia in rats and monkeys, and also augments long-term potentiation (LTP) in the mossy fiber-CA3 pathway in guinea-pig hippocampal slices. Our recent studies have further suggested that somatostatin activation could be a primary mechanism of the pharmacological action of FK960. To clarify the mode of action of FK960 on somatostatinergic neurotransmission, FK960 was examined for its effects on somatostatin release from rat hippocampal slices. FK960 significantly enhanced high K(+)-evoked release, but not basal release, of somatostatin with similar concentration-dependency to its LTP augmenting action. On the other hands, FK960 had no effects on the release of neurotransmitters such as acetylcholine, 5-HT, D-aspartate or GABA from hippocampal slices. Our results provide compelling evidence that FK960 exerts specific and facilitatory actions on neural mechanisms involved in the activity-dependent release of somatostatin from nerve terminals of the hippocampus. These results also strengthen the view that FK960 regulates cognitive functions and augments LTP through an activation of the somatostatinergic nervous system in the hippocampus.