RT Journal Article
SR Electronic
T1 Modulation of Ca<sup>2+</sup>Channel Currents by a Novel Antidementia Drug<em>N</em>-(4-Acetyl-1-piperazinyl)-<em>p</em>-fluorobenzamide Monohydrate (FK960) in Rat Hippocampal Neurons
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 120
OP 126
DO 10.1124/jpet.103.057687
VO 308
IS 1
A1 Feng Wang
A1 Nobuya Matsuoka
A1 Seitaro Mutoh
A1 Shuji Kaneko
YR 2004
UL http://jpet.aspetjournals.org/content/308/1/120.abstract
AB 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 GABABreceptor. 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 μM 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. The American Society for Pharmacology and Experimental Therapeutics