Lithium selectively inhibits muscarinic receptor-stimulated inositol tetrakisphosphate accumulation in mouse cerebral cortex slices.
The in vitro effects of Li on agonist- and depolarization-stimulated accumulation of inositol phosphates were determined in mouse cerebral cortex slices. Of the agents examined, only the cholinergic agonist carbachol produced a significant accumulation of inositol tetrakisphosphate (InsP4) in the absence of Li. Lithium at 5 mM enhanced the accumulation of inositol monophosphate (InsP1) and inositol bisphosphate (InsP2) due to all the stimuli used and potentiated inositol trisphosphate (InsP3) accumulation due to histamine and noradrenaline, although at lower Li concentrations, carbachol-stimulated InsP3 accumulation was reduced. Li also enhanced InsP4 accumulation in the presence of noradrenaline, histamine, and elevated KCl level but, in marked contrast, reduced carbachol-stimulated InsP4 accumulation with an IC50 of 100 microM. There was a significant time delay between the initiation of carbachol stimulation and the beginning of the InsP4 inhibition due to Li. The phorbol ester 4 beta-phorbol 12 beta-myristate 13 alpha-acetate did not mimic the effects of Li. The results suggest that muscarinic receptor-mediated InsP4 production might be one of the targets for the therapeutic action of Li.
Whitworth
P
P
Department of Physiology and Pharamcology, Medical School, Queen's Medical Centre, Nottingham, England.
Kendall
D A
DA
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism*; D007700:Kinetics; D008094:Lithium / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D011189:Potassium Chloride / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D013403:Sugar Phosphates / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D007295:Inositol Phosphates; D011976:Receptors, Muscarinic; D013403:Sugar Phosphates; D011189:Potassium Chloride; D002217:Carbachol; D008094:Lithium; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate