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Research ArticleNEUROPHARMACOLOGY

Modulation of Ca2+Channel Currents by a Novel Antidementia DrugN-(4-Acetyl-1-piperazinyl)-p-fluorobenzamide Monohydrate (FK960) in Rat Hippocampal Neurons

Feng Wang, Nobuya Matsuoka, Seitaro Mutoh and Shuji Kaneko
Journal of Pharmacology and Experimental Therapeutics January 2004, 308 (1) 120-126; DOI: https://doi.org/10.1124/jpet.103.057687
Feng Wang
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Nobuya Matsuoka
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Seitaro Mutoh
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Shuji Kaneko
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Abstract

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.

Footnotes

  • DOI: 10.1124/jpet.103.057687.

  • ABBREVIATIONS:ACh, acetylcholine; LTP, long-term potentiation; PTX, pertussis-toxin; GTPγS, guanosine 5′-O-(3-thio)triphosphate; H-7, 1-(5-isoquinoline sulfonyl)-2-methylpiperazine; PKC, protein kinase C.

    • Received July 28, 2003.
    • Accepted October 8, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 308 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 308, Issue 1
1 Jan 2004
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Research ArticleNEUROPHARMACOLOGY

Modulation of Ca2+Channel Currents by a Novel Antidementia DrugN-(4-Acetyl-1-piperazinyl)-p-fluorobenzamide Monohydrate (FK960) in Rat Hippocampal Neurons

Feng Wang, Nobuya Matsuoka, Seitaro Mutoh and Shuji Kaneko
Journal of Pharmacology and Experimental Therapeutics January 1, 2004, 308 (1) 120-126; DOI: https://doi.org/10.1124/jpet.103.057687

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Research ArticleNEUROPHARMACOLOGY

Modulation of Ca2+Channel Currents by a Novel Antidementia DrugN-(4-Acetyl-1-piperazinyl)-p-fluorobenzamide Monohydrate (FK960) in Rat Hippocampal Neurons

Feng Wang, Nobuya Matsuoka, Seitaro Mutoh and Shuji Kaneko
Journal of Pharmacology and Experimental Therapeutics January 1, 2004, 308 (1) 120-126; DOI: https://doi.org/10.1124/jpet.103.057687
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