Lithium treatment of affective disorders; effects on the cyclic AMP and inositol phospholipid signalling pathways’

Date
1992
Authors
Sillence, Daniel J.
Downes, C. P.
Journal Title
Journal ISSN
ISSN
Volume Title
Publisher
Elsevier
Peer reviewed
Yes
Abstract
The effects of lithium (Li+) on the adenylyl cyclase and inositol phospholipid receptor signalling pathways were compared directly in noradrenergic and carbachol stimulated rat brain cortical tissue slices. Li+ was a comparatively weak inhibitor of noradrenaline-stimulated cyclic AMP accumulation with an IC50 of approx. 20 mM. By contrast, half-maximal effects of Li+ on inositol monophosphate (InsP) accumulation in [3H]inositol labelled tissue slices occurred at about 1 mM. A similar IC50 for Li+ of about 1 mM was also obtained for noradrenaline-stimulated accumulation of CMP-phosphatidate (CMPPA), a sensitive indicator of intracellular inositol depletion, in tissue slices that had been prelabelled with [3H]cytidine. The effect of myo-inositol (inositol) depletion on the prolonged activity of phosphoinositidase C (PIC) was examined in carbachol-stimulated cortical slices using a novel mass assay for InsP. Exposure to a maximal dose of carbachol for 30 min in the presence of 5 mM Li+ caused a 10-fold increase in the level of radioactivity associated with the InsP fraction, but only a 2-fold increase in InsP mass. During prolonged incubations in the presence of both carbachol and Li+ the accumulation of InsP mass was enhanced if 30 mM inositol was included in the medium. The results are compatible with the inositol depletion hypothesis of Li+ action but do not support the concept that adenylyl cyclase or guanine nucleotide dependent proteins represent therapeutically relevant targets of this drug.
Description
Keywords
Inositol Phosphates
Citation
Sillence, D.J. and Downes, C.P. (1992) Lithium treatment of affective disorders; effects on the cyclic AMP and inositol phospholipid signalling pathways. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1138 (1), pp. 46-52
Research Institute
Leicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)