Augmentation of lithium's behavioral effect by inositol uptake inhibitors

  title={Augmentation of lithium's behavioral effect by inositol uptake inhibitors},
  author={Haim Einat and Ora Kofman and O. Itkin and R. J. Lewitan and Robert H. Belmaker},
  journal={Journal of Neural Transmission},
Summary. Lithium inhibits the enzyme inositol monophosphatase and thus obstructs the enzymatic degradation of inositol triphosphate (IP3) to inositol in the phosphate-phosphoinositide (PIP) cycle. This inhibition may result in reduced availability of the second messengers IP3 and DAG that are derivates of the PIP cycle, and this action is currently a leading hypothesis regarding lithium's therapeutic and prophylactic effect in affective disorders. Inositol is also available to the cell by… 
The high affinity inositol transport system--implications for the pathophysiology and treatment of bipolar disorder.
It is concluded that downregulation of SMIT could represent a common mechanism of action of mood stabilizers: inhibition of myo-inositol uptake that proceeds via the sodium/myo- inositol cotransport (SMIT).
Nordidemnin potently inhibits inositol uptake in cultured astrocytes and dose‐dependently augments lithium's proconvulsant effect in vivo
An extremely high potency of nordidemnin is demonstrated as an inhibitor of myo‐inositol uptake in primary cultures of mouse astrocytes and the dose‐response correlation of a nordemnin‐induced decrease in the latency before appearance of seizures in the lithium‐pilocarpine test after intracerebroventricular injection of minute samples of virtually isotonic saline solution is determined.
Epi-Inositol and inositol depletion: Two new treatment approaches in affective disorder
It is proposed that an inositol-free diet will augment lithium action in mania by enhancing restriction of inositole, and its effect was stronger than that of myoinositol.
Defining the neuromolecular action of myo-inositol Application to obsessive–compulsive disorder
Myo-inositol-1-phosphate (MIP) synthase inhibition: in-vivo study in rats
This study shows that MIP synthase inhibition does not replicate or augment the effects of lithium in the inositol sensitive pilocarpine-induced seizures model, suggesting a lack of effects may stem from the low contribution of de-novo synthesis to cellular inositols supply or to the inhibition of the de- novo synthesis by lithium itself.
Bipolar Disorders and Lithium: Pharmacokinetics, Pharmacodynamics, Therapeutic Effects and Indications of Lithium: Review of Articles
  • Medicine
  • 2016
Lithium is a mood stabilizer which is approved for use in acute and maintenance mania. It is the first medications approved for the treatment of bipolar disorders. The drug has narrow therapeutic
Lithium therapy and signal transduction.
A Model of Inositol Compartmentation in Astrocytes Based Upon Efflux Kinetics and Slow Inositol Depletion after Uptake Inhibition
It is suggested that the large, slowly exchanging compartment is largely membrane-associated and participating in signaling via the phosphatidylinositide second messenger system, whereas inositol functioning as an osmolyte is distributed in the cytosol and located in one or both of the compartments showing a faster release.


Behavioral evidence for the existence of two pools of cellular inositol
Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands.
The ability of Li+ to greatly amplify the agonist-dependent accumulation of myo-inositol 1-phosphate offers a novel technique for identifying those receptors that function by hydrolysing phosphatidyl inositol, which may help reset the sensitivity of those multifunctional receptors that generate second messengers such as Ca2+, cyclic GMP and the prostaglandins.
The Effect of Lithium on Inositol Phosphate Metabolism
This chapter reviews the action of lithium on a target which fulfills the preceding criteria reasonably well, that is, the phosphoinositide cycle, and discusses two main issues; first, whether the actions of Lithium on the cycle can be explained by inhibition of a single step in the pathway, for example, the inositol monophosphatase enzyme; and second, whether interference with the phosphate cycle provides a convincing explanation for the therapeuticaction of lithium.
Lithium and inositol lipid-linked signalling mechanisms
The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain.
Analysis of the convulsant-potentiating effects of lithium in rats
Dual effects of nordidemnin on WRK1 cells: inhibition of phosphoinositide metabolism and cell proliferation.
Results suggest that NorD might interfere with WRK1 cell growth by inhibiting phosphoinositide turnover by blocking the myoinositol transporter and, by a consequence, the pool of inositol lipids.
The Mechanism of Muscarinic Receptor‐Stimulated Phosphatidylinositol Resynthesis in 1321N1 Astrocytoma Cells and Its Inhibition by Li+
The preferential capacity of Li+ to impair stimulated phosphoinositide turnover in systems expressing low cellular inositol can be attributed to its ability to attenuate the stimulated rise in inositl concentrations on which such systems selectively depend to trigger accelerated PtdIns resynthesis.
The characteristics, capacity and receptor regulation of inositol uptake in 1321N1 astrocytoma cells.
The results imply that receptors which couple to phospholipase C may mediate inhibition of inositol uptake via protein kinase C in resting and stimulated cells.