8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid stimulates GABA release from interneurons projecting to CA1 pyramidal neurons in the rat hippocampus via pre-synaptic α7 acetylcholine receptors

Nicotinic acetylcholine (ACh) receptors, such as alpha 7, alpha 3 beta 4 and alpha 4 beta 2 receptors in the hippocampus, are suggested to modulate neurotransmitter release. 8-[2-(2-Pentyl-cyclopropylmethyl)cyclopropyl]- octanoic acid (DCP-LA) ( 100 nM), a linoleic acid derivative, potentiated responses of alpha 7, alpha 3 beta 4 and alpha 4 beta 2 ACh receptors expressed in Xenopus oocytes that are blocked by 3-(1-[dimethylaminopropyl]indol-3-yl)-4-[indol-3-yl] maleimide (GF109203X), a selective inhibitor of protein kinase C (PKC), except for alpha 3 beta 4 ACh receptors. DCP-LA enhanced the nicotine-triggered release of GABA from rat hippocampal slices in the presence of tetrodotoxin in a bell-shaped dose-dependent manner at concentrations ranging from 10 nM to 10 mu M, although DCP-LA by itself had no effect on GABA release. The DCP-LA action was inhibited by GF109203X or alpha-bungarotoxin, an inhibitor of alpha 7 ACh receptors, but not by mecamylamine or dihydro-beta-erithroidine, an inhibitor of alpha 3 beta 4 and alpha 4 beta 2 ACh receptors. A similar effect on GABA release was obtained with 12-O-tetradecanoylphorbol 13-acetate, a PKC activator. DCP-LA ( 100 nM) also enhanced GABA release triggered by choline, an agonist of alpha 7 ACh receptors, but not 3-[2(s)-azetidinylmethoxy] pyridine, an agonist of alpha 4 beta 2 ACh receptors. In addition, DCP-LA ( 100 nM) increased the rate of nicotine-triggered GABA(A) receptor-mediated miniature inhibitory post- synaptic currents, monitored from CA1 pyramidal neurons of rat hippocampal slices, and the effect was also inhibited by GF109203X or alpha-bungarotoxin but not by mecamylamine. Thus, the results of the present study indicate that DCP-LA stimulates GABA release by enhancing activity of pre-synaptic alpha 7 ACh receptors present on the GABAergic terminals of interneurons that transmit to CA1 pyramidal neurons via a PKC pathway.