N-(4-Acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate (
FK960), a novel antidementia
drug, has been demonstrated to ameliorate
memory deficits in various experimental models of
dementia. This
drug selectively increases
somatostatin release from hippocampal slices and augments long-term potentiation (LTP) in the CA3 area of the hippocampus. In the present study, the effects of
FK960 on voltage-activated Ca2+ channels were investigated in acutely isolated rat hippocampal neurons, using whole-cell patch-clamp technique to clarify the cellular mode of action of
FK960. Application of
somatostatin significantly reduced Ca2+ currents via
G protein-coupled signaling pathways. This inhibitory effect was significantly abolished by
FK960 when applied in combination. In contrast,
FK960 showed only modest inhibition on the reduction in Ca2+ currents produced by
baclofen, an agonist of GABAB receptor. Intracellular application of the
protein kinase inhibitor H-7 did not alter
somatostatin-induced inhibition and had no significant effect on blockade by
FK960. In addition, application of
FK960 alone produced modest but apparent increases in Ca2+ currents without significant changes in the activation kinetics of the channels. The dose-response relationship on
calcium current enhancement was bell-shaped with a maximum effect at 0.1 microM
FK960, the same concentration as that for increasing on
somatostatin release and CA3-LTP. These results show that
FK960 reverses
G protein-dependent inhibition of Ca2+ currents by
somatostatin in hippocampal neurons. Enhancement of Ca2+ currents by
FK960 may be due to its modulatory actions on Ca2+ channels, rather than removal of
G protein-inhibited tonic currents. Together, these mechanisms may be involved in the selective effects of
FK960 on
somatostatin release, excitatory transmission, and synaptic plasticity in the hippocampus.