FK960, a novel potential anti-dementia drug, enhances high K+-evoked release of somatostatin from rat hippocampal slices

We have demonstrated that FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzami de monohydrate], a novel putative anti-dementia drug of piperazine derivati ve, ameliorates memory deficits in a variety of animal models of dementia i n rats and monkeys, and also augments long-term potentiation (LTP) in the m ossy fiber-GAS pathway in guinea-pig hippocampal slices. Our recent studies have further suggested that somatostatin activation could be a primary mec hanism of the pharmacological action of FK960. To clarify the mode of actio n of FK960 on somatostatinergic neurotransmission, FK960 was examined for i ts effects on somatostatin release from rat hippocampal slices. FK960 signi ficantly enhanced high K+-evoked release, but not basal release, of somatos tatin with similar concentration-dependency to its LTP augmenting action. O n 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 faci litatory actions on neural mechanisms involved in the activity-dependent re lease of somatostatin from nerve terminals of the hippocampus. These result s also strengthen the view that FK960 regulates cognitive functions and aug ments LTP through an activation of the somatostatinergic nervous system in the hippocampus. (C) 2001 Elsevier Science B.V. All rights reserved.