Comparative effects of lithium on the phosphoinositide cycle in rat cerebral cortex, hippocampus, and striatum.
The effects of lithium on muscarinic cholinoceptor-stimulated phosphoinositide turnover have been investigated in rat hippocampal, striatal, and cerebral cortical slices using [3H]inositol or [3H]cytidine prelabelling and inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4] mass determination methods. Carbachol addition resulted in maintained increases in Ins(1,4,5)P3 and Ins(1,3,4,5)P4 mass levels in hippocampus and cerebral cortex, whereas in striatal slices these responses declined significantly over a 30-min incubation period. Carbachol-stimulated Ins(1,4,5)P3 and Ins(1,3,4,5)P4 accumulations were inhibited by lithium in all brain regions studied in a time- and concentration-dependent manner. For example, in hippocampal slices significant inhibitory effects of LiCl were observed at times > 10 min after agonist challenge; IC50 values for inhibition of agonist-stimulated Ins(1,4,5)P3 and Ins(1,3,4,5)P4 accumulations by lithium were 0.22 +/- 0.09 and 0.33 +/- 0.13 mM, respectively. [3H]CMP-phosphatidate accumulation increased in all brain regions when slices were stimulated by agonist and lithium. The ability of myo-inositol to reverse these effects, as well as lithium-suppressed Ins(1,4,5)P3 accumulation, implicates myo-inositol depletion in the action of lithium in the hippocampus and cortex at least. The results of this study suggest that although significant differences in the magnitude and time courses of changes in inositol (poly)phosphate metabolites occur in different brain regions, lithium evokes qualitatively similar enhancements of [3H]inositol monophosphate and [3H]-CMP-phosphatidate levels and inhibitions of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 accumulations. However, the inability of striatal slices to sustain carbachol-stimulated inositol polyphosphate accumulation in the absence of lithium and the inability to reverse effects with myo-inositol may indicate differences in phosphoinositide signalling in this brain region.
Department of Pharmacology and Therapeutics, University of Leicester, England.
S
S
Jenkinson
N
N
Patel
S R
SR
Nahorski
R A
RA
Challiss
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D003568:Cytidine Monophosphate / Q000031:analogs & derivatives / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D007294:Inositol / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D009994:Osmolar Concentration; D010712:Phosphatidic Acids / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats
D007295:Inositol Phosphates; D010712:Phosphatidic Acids; D010716:Phosphatidylinositols; D007294:Inositol; D002217:Carbachol; D008094:Lithium; D003568:Cytidine Monophosphate