Behavioral Reversal of Lithium Effects by Four Inositol Isomers Correlates Perfectly with Biochemical Effects on the PI Cycle: Depletion by Chronic Lithium of Brain Inositol Is Specific to Hypothalamus, and Inositol Levels May be Abnormal in Postmortem Brain from Bipolar Patients

Abstract

The inositol depletion hypothesis of lithium (Li) action has been criticized, because depletion of inositol after chronic Li treatment has not been reproducible, effects of inositol to reverse Li-induced behaviors occurred also with epi-inositol, a unnatural isomer, and because inositol is ubiquitous in brain and hard to relate to the pathogenesis of affective disorder. Therefore, we review our studies showing that lithium depletion of brain inositol occurs chronically in the hypothalamus, a region not previously examined; that behavioral effects of four different inositol isomers including epi-inositol correlate perfectly with their biochemical effects; and that inositol in postmortem human brain is reduced by 25% in frontal cortex of bipolars and suicides as compared with controls. Because inositol in postmortem brain is reduced and not increased in bipolar patients Epi-inositol; Myo-inositol; Bipolar disorder; Frontal cortex Lithium (Li ϩ ) has therapeutic and prophylactic effects on both the manic and depressive phases of bipolar affective disorder; however, the mechanism of Li's therapeutic action is not clear. Several biochemical actions have been attributed to Li ϩ (Wood and Goodwin 1987), but none has been incontrovertibly associated with its effects on behavior or mood.Li ϩ inhibits the dephosphorylation of four of the inositol monophosphates as well as two inositol biphosphates, thereby increasing brain levels of inositol monophosphate and two biphosphates and reducing levels of myo-inositol (Allison et al. 1976;Allison et al. 1980;Honchar et al. 1989;Sherman et al. 1981Sherman et al. , 1985b. These effects are attributable to Li ϩ 's inhibition of inositol monophosphatase Moscovich et al. 1990) and inositol polyphosphate 1-phosphatase (Inhorn and Majerus 1987). In rats, lithium chloride (LiCl), 10 meq/kg, reduced brain inositol levels by 30% and increased inositol monophosphate levels 20-fold after 6 h (Allison et al. 1976(Allison et al. , 1980 and 40-fold after 24 h (Sherman et al. 1985b . To ascertain if Li ϩ 's inhibition of inositol monophosphatase is relevant to its therapeutic effects in patients with affective disorders, it is critical to demonstrate that behavioral effects of Li ϩ are also reversed by myo-inositol. Because myo-inositol does not easily penetrate the blood-brain barrier when injected systemically (Spector and Lorenzo 1975), it is preferable to inject myo-inositol directly into the brain. ICV myoinositol was found to reverse inhibition of rearing in rats induced by an acute injection of Li ϩ (Kofman and Belmaker 1993). INOSITOL REVERSES Li-PILOCARPINE SEIZURESOne of the most robust behavioral effects of Li ϩ is that normally subconvulsant doses of muscarinic agonists will induce limbic seizures in rats pretreated with lithium (Honchar et al. 1983). Induction of Li ϩ -pilocarpine seizures is concomitant with a reduction in cortical myo-inositol levels and an elevation of inositol monophosphate, which is about 10-fold greater than the effects elicited by either Li ϩ or pilocar...

The Pleckstrin Homology Domain of Diacylglycerol Kinase η Strongly and Selectively Binds to Phosphatidylinositol 4,5-Bisphosphate

“…In the brain, DGK is enriched in the dentate gyrus of the hippocampus and the Purkinje cells of the cerebellum (26), which are known to be associated with bipolar disorder (46 -48). A common treatment for bipolar disorder is a mood stabilizer, lithium, which attenuates PI turnover (49). Therefore, DGK may regulate the pathogenesis of bipolar disorder through the PH-dependent binding to PI(4,5)P 2 generated by PI turnover in the dentate gyrus and the Purkinje cells.…”

Anti-bipolar therapy: mechanism of action of lithium

“…Nonetheless, an intriguing outgrowth of the inositol depletion hypothesis has been the novel application of inositol as a pharmacological agent which has shown promising utility in animal models and therapeutic applications. 13,59 Additionally, the concentration and uptake of inositol differs among regions of rat brain and reduced inositol levels in rat brain following lithium administration were recently reported to be limited to the hypothalamus, [60][61][62] and lithium was also found to reduce inositol in astrocytes. 63 Thus, each of these factors, brain region, celltype, and endogenous inositol cycles, introduces complexities in the relationship between lithium and inositol which have made it difficult to define precisely how lithium's inhibition of inositol monophosphatase affects phosphoinositide signaling.…”

Acute Intracerebroventricular Inositol Does Not Reverse the Effect of Chronic Lithium Treatment in the Forced Swim Test

“…Myo- inositol reversal of lithium's effects has previously been demonstrated in a number of behavioral and neurochemical paradigms including hypersensitivity to pilocarpine-induced seizures [14,16], suppression of rearing behavior [17], stabilization of neuronal growth cones [18,19] and induction of autophagy [20]. In the present study we hypothesized stereospecific reversal of lithium's effect by myo -inositol in the FST.…”

“…In order to control for the possible osmotic effects of the compound and in order to study the stereospecificity of the investigated effect, the effect of myo -inositol ICV administration was compared to that of chiro- inositol, previously shown to be behaviorally and biochemically inactive in the lithium-pilocarpine seizures paradigm and the phosphatidylinositol cycle, respectively [14]. …”