Disruption by Lithium of Phosphoinositide Signalling in Cerebellar Granule Cells in Primary Culture

Abstract

Mild depolarisation (20 mM KCI) synergistically enhances the ability of a muscarinic agonist to activate phosphoinositide turnover and to elevate inositol 1,4,5‐trisphosphate [Ins(1,4,5)P3] in cerebellar granule cells in primary culture. The effects of lithium on this intense stimulation of phosphoinositide turnover was studied. Lithium causes depletion of cytoplasmic inositol and phosphoinositides, which results in the inhibition of phosphoinositide turnover within 15 min and the return of Ins(1,4,5)P3 to basal levels at this time. This inhibition could not be reversed by culturing and preincubating cerebellar granule cells in concentrations of inositol similar to those detected in the CSF. Inositol concentrations substantially in excess of those in the CSF not only reversed the effects of lithium on stimulated Ins(1,4,5)P3 levels, but significantly enhanced this level in comparison with stimulation in the absence of lithium. sn‐1,2‐Diacylglycerol elevation during stimulated phosphoinositide turnover was also disrupted by lithium, but in contrast to Ins(1,4,5)3, the presence of lithium resulted in a transient enhancement of the elevation evoked by carbachol plus mild KCI depolarisation, which was reversed by 500 µM inositol, but not by 200 µM inositol. The implications of these phenomena in relation to the mechanism of action of lithium in the treatment of manic depression are discussed.

Lithium and fluoxetine regulate the rate of phosphoinositide synthesis in neurons: a new view of their mechanisms of action in bipolar disorder

“…In support of this hypothesis, lithium has previously been shown to decrease steady-state levels of PIns in neurons: these effects, however, were only seen when PIP 2 hydrolysis was hyper-stimulated for a prolonged period with the cholinergic agonist carbachol 10,11 , and this extreme pharmacological manipulation is unlikely to be relevant to normal brain function. Other studies that argue against a therapeutic role for IMPase inhibition have focussed on lithium’s effects on brain inositol and/or PIns levels.…”

“…Most previous studies of lithium’s effects in PIns synthesis used either cell lines that expressed the high capacity SMITs 29 or cerebellum granule cell neurons in which the status of SMIT-1 was not documented 10,11 ; these cells have mM levels of intracellular inositol 30,31 , which has contributed to the scepticism about inhibition of IMPase leading to inositol depletion as relevant to lithium’s therapeutic effects. Thus, a reinvestigation of the effect of lithium on inositol and PIns metabolism in primary neurons lacking SMITs is needed.…”

Decreased Anterior Cingulate Myo-inositol/Creatine Spectroscopy Resonance with Lithium Treatment in Children with Bipolar Disorder

“…Lithium's inhibitory action on receptor-mediated signal-transduction pathways has been demonstrated in vitro (Atack et al 1995) showing that it reduces myoinositol levels by non-competitively inhibiting the enzyme inositol monophosphate, a catalyst for converting inositol monophosphate hydroxyls to myo-inositol (Manji et al 1996). Since the phosphoinositide cycle (PI) regulates a wide variety of neuronal functions, including intracellular calcium mobilization and protein kinase C (PKC) activity (Feldman et al 1997), lithiuminduced modification of the PI cycle has been proposed as a potential therapeutic mechanism underlying its mood-stabilizing effect (Berridge et al 1982;del Rio et al 1998;Murray and Greenberg 1997;Soares et al 1999). Although brain tissue can synthesize myo-inositol de novo , the ability of neurons to maintain a steady-state supply of cytosolic myo-inositol appears to be crucial to the resynthesis of phosphoinositides, and, conceivably, to the membrane receptor response to stimulation and neuronal homeostasis.…”

“…It is apparent that lithium exerts an effect on intracellular second-messenger systems in which activated receptorligand complexes stimulate the turnover of inositolcontaining phospholipids (del Rio et al 1998;Feldman et al 1997;Murray and Greenberg 1997;Soares et al 1999). Lithium's inhibitory action on receptor-mediated signal-transduction pathways has been demonstrated in vitro (Atack et al 1995) showing that it reduces myoinositol levels by non-competitively inhibiting the enzyme inositol monophosphate, a catalyst for converting inositol monophosphate hydroxyls to myo-inositol (Manji et al 1996).…”

Effects of Different Periods of Lithium Pretreatment and Aminoglycoside Antibiotics on Apomorphine‐Induced Yawning in Rats

“…Our previous investigations have also shown that lithium can decrease penile erection induced by activation of the dopaminergic system (Dehpour et al 1995;Sharifzadeh et al 1996) and yawning response induced by cholonergic activation (Sharifzadeh et al 1997). It has been reported that lithium causes depletion of cytoplasmic inositol and phosphoinositide turnover (Hallcher & Sherman 1980;Del-Rio et al 1998), which could interfere with the re-synthesis of phosphatidyl inositol bisphosphate, thus influencing the signaling mechanisms operating through the phosphoinositide system. Lithium has also been shown to attenuate protein kinase C function (Bitran et al 1995).…”