Lithium Effects on Inositol Phospholipids and Inositol Phosphates: Evaluation of an In Vivo Model for Assessing Polyphosphoinositide Turnover in Brain

Abstract

Administration of lithium chloride to rats injected intracerebrally with [3H]inositol led to time- and dose-dependent increases in levels of labeled inositol monophosphates in brain. Quantitative analysis of the inositol phosphates by ion chromatography revealed 37- and 20-fold increases in the mass of myo-inositol 1-phosphate and 4-phosphate, respectively, at 4 h intraperitoneal after injections of 6 mEq/kg of lithium chloride. Albeit to a much lesser extent, lithium administration also resulted in an increase in the level of myo-inositol, 1,4-bisphosphate in brain. The lithium-induced increase in content of labeled inositol monophosphates was marked by a concomitant decrease in content of labeled inositol, and after injections of high doses of lithium, e.g., 10 mEq/kg, this was followed by a general decrease in labeling of the inositol phospholipids. In general, animals injected with [3H]inositol but not lithium did not reveal obvious differences in labeling of inositol monophosphates on stimulation by mecamylamine or pilocarpine. However, when animals were injected with [3H]inositol and then lithium, there were large increases in the levels of labeled inositol monophosphates on administration of these compounds. Administration of atropine to the lithium-treated mice led to a partial reduction in the amount of labeled inositol monophosphates accumulated due to the administration of lithium alone. Furthermore, atropine was able to block the pilocarpine-induced increase in level of labeled inositol monophosphates. These results demonstrate the suitable use of the radiotracer technique together with lithium administration for assessing the effects of drugs and receptor agonists on the signaling system involving polyphosphoinositide turnover in brain.

Chronic treatment with both lithium and sodium valproate may normalize phosphoinositol cycle activity in bipolar patients

“…Animal studies have shown that, in vitro and in vivo, lithium administration leads to a decrease in myo-inositol and an increase in the inositol monophosphate precursors (Sherman et al, 1985;Godfrey et al, 1989;Hirvonin, 1991;Sun et al, 1992). Adding to these findings we have found that in animals sodium valproate also decreases the concentration of myo-inositol and increases the concentration of inositol monophosphates in rat brain, suggesting the possibility of a similar mechanism of action (O'Donnell et al, 2000).…”

“…One other point to note is that a decrease in myoinositol is often seen in rat studies following lithium treatment (Sherman et al, 1985;Godfrey et al, 1989;Hirvonen 1991;Sun et al, 1992) and we have recently found decreased myo-inositol concentrations in rats following both lithium and valproate treatment (O'Donnell et al, 2000). However, it is possible that these differences may be explained by the fact that these are ex vivo studies which firstly may have higher sensitivity than the in vivo studies and secondly may use significantly higher doses of medications than those used in human studies.…”

Chronic Lithium‐Induced Down‐Regulation of MARCKS in Immortalized Hippocampal Cells: Potentiation by Muscarinic Receptor Activation

“…In recent years several lines of investigation have lent support to this hypothesis. Numerous studies performed in various cell systems, in both cells and the brain, have demonstrated lithium-induced effects on the receptor-mediated P1 hydrolysis pathway, including decreased cellular inositol levels (Allison et al, 1976) and significantly elevated levels of IPs (Dixon et al, 1992;Sun et al, 1992;Atack et al, 1993;Ishima et al, 1993), CMP-PA (Godfrey, 1989;Kennedy et al, 1990;Watson et al, 1990;Atack et al, 1993;Stubbs and Agra-noff~1993;Jenkinson et al, 1994;Lenox and Watson, 1994), phosphatidic acid, and DAG (Drummond and Raeburn, 1984;Downes and Stone, 1986;Brami et a!., 1991Brami et a!., , 1993 (for review, also see Manji et al, 1995). The IC.~0 of lithium for IMPase (0.8 mM) is within the range (0.6-1.2 mM) of therapeutic plasma lithium levels required for treatment of affective disorders (Hallcher and Sherman, 1980).…”

Cross‐talk between the TGFβ and Wnt signaling pathways in murine embryonic maxillary mesenchymal cells

“…Whether this indicates that Wnt-3a utilizes alternate pathways, in addition to the canonical pathway to inhibit cell proliferation, or that LiCl is not as efficacious as Wnt-3a is unclear. LiCl may also have other cellular effects, such as increasing inositol lipids, which may influence its efficacy in this assay [53]. These data do suggest, however, that Wnt-3a can inhibit proliferation of MEMM cells, in part, through control of b-catenin levels.…”