Involvement of protein kinase C activation in regulation of acetylcholine release from rat hippocampal slices by minaprine.

Abstract

Involvement of protein kinase C (PKC) activation in the regulation of acetylcholine (ACh) release from rat hippocampal slices by minaprine, [3(2-morpholinoethylamino)-4-methyl-6-phenylpyridazine] was investigated. Phorbol esters such as 4 beta-phorbol 12,13-dibutylate (PDBu) and 12-o-tetradecanoylphorbol 13-acetate (TPA) enhanced high K(+)-evoked [3H]ACh release from rat hippocampal slices. The enhancing effect of phorbol ester was attenuated by PKC inhibitors, staurosporine and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7). However, the inactive phorbol analogue, 4 alpha-phorbol 12,13-didecanoate (PDD) had no effect on [3H]ACh release. Minaprine and 4-aminopyridine (4-AP) attenuated the inhibitory effect of 5-hydroxytryptamine (5-HT) on high K(+)-evoked [3H]ACh release from rat hippocampal slices. The attenuating effect of minaprine on the inhibition of [3H]ACh release by 5-HT was prevented by staurosporine, while that of 4-AP was not influenced. Furthermore, PDBu blocked voltage-dependent, rapidly inactivating 42K efflux from rat brain synaptosomes. These results suggest that minaprine attenuates the inhibitory effect of 5-HT on ACh release via PKC activation in rat hippocampus, and that the blockade of the K+ channel with PKC activation might be involved in the action of minaprine.