Tricyclic Antidepressants, Mianserin, and Ouabain Stimulate Inositol Phosphate Formation in Vitro in Rat Cortical Slices

The ability of tricyclic antidepressants, monoamine oxidase inhibitors, mianserin and ouabain to stimulate hydrolysis of inositol phosphates was examined in rat cerebral cortex slices using a direct assay which involves labelling with [3H]inositol and assaying [3H]inositol phosphates in the presence of lithium. Desimipramine, imipramine, chlorimipramine, mianserin, and ouabain stimulated [3H]inositol phosphate accumulation in a concentration-dependent manner. The monoamine oxidase inhibitors, pargyline and nialamide were without effect. The stimulation of [3H]inositol phosphate accumulation caused by the various substances was not blocked by the antagonists prazosin, ketanserin, atropine, or mepyramine. In contrast, the antagonists prazosin, ketanserin, atropine and mepyramine selectively blocked stimulation of [3H]inositol phosphate accumulation caused by noradrenaline, serotonin, carbachol and histamine respectively. When desimipramine was substituted for lithium in the assay procedure, carbachol was ineffectual in stimulating [3H]inositol phosphate accumulation. In these experiments the control (unstimulated) values were much higher than in the normal (when lithium is present) assay procedure. Desimipramine is quite effective in stimulating [3H]inositol phosphate accumulation either in the presence or absence of lithium in the incubation medium. This is not the case for carbachol where it was essential to have lithium in the incubation medium in order to obtain a stimulation of [3H]inositol phosphate accumulation. Furthermore, in the case of carbachol stimulation, most of the radioactivity was associated with a peak corresponding to inositol monophosphate, while for desimipramine stimulation two clear peaks corresponding to inositol monophosphate and inositol bisphosphate were apparent.