Role of glial glutamate transporters in the facilitatory action of FK960 on hippocampal neurotransmission.

We found previously that N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate (FK960) facilitated hippocampal neurotransmission in the dentate gyrus of rat hippocampal slices. The present study was conducted to understand the mechanism underlying the facilitatory action of FK960. The facilitation was inhibited by H-89, an inhibitor of cAMP-dependent protein kinase (PKA), but it was not affected by cycloheximide, a protein synthesis blocker. In cultured rat hippocampal neurons, the drug had no effect on either spontaneous miniature excitatory postsynaptic currents or whole-cell membrane currents evoked by glutamate, kainate, or NMDA, suggesting that the facilitatory action of FK960 is not caused by increasing presynaptic transmitter release or excitatory postsynaptic conductances. FK960 inhibited responses of the glial glutamate transporter, GLT-1, expressed in Xenopus oocytes, and a similar effect was found with cultured rat astrocytes. The FK960 action was inhibited in the presence of H-89. The results of the present study thus suggest that FK960 facilitates hippocampal neurotransmission by inhibiting GLT-1 glial glutamate reuptake via a PKA pathway, thereby increasing synaptic glutamate concentrations.