Systemic Cholinergic Agents Induce Seizures and Brain Damage in Lithium-Treated Rats

Honchar, Michael P.; Olney, John W.; Sherman, William R.

doi:10.1126/science.6301005

Cited by 345 publications

(167 citation statements)

References 32 publications

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“…Multiple rodent studies have shown that lithium treatment causes a sensitization to pilocarpine-induced seizures (Honchar et al, 1983;. Moreover, this enhanced sensitivity was shown to be reversed by replenishment of myo-inositol and not by its stereoisomer chiro-inositol that does not enter the PI cycle .…”

Section: Discussionmentioning

confidence: 99%

“…One in vivo demonstration of a lithium effect dependent on inositol is lithium pilocarpine-induced seizures. Rodents treated with lithium acutely or chronically are exquisitely sensitive to pilocarpine leading to a unique limbic seizure behavior (Honchar et al, 1983). This behavior is stereospecifically reversed by intracerebroventricular myo-inositol but not by its stereoisomer chiro-inositol, that does not enter the PI cycle .…”

Section: Introductionmentioning

confidence: 99%

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IMPA1 is Essential for Embryonic Development and Lithium-Like Pilocarpine Sensitivity

Cryns¹,

Shamir

Acker

et al. 2007

Neuropsychopharmacol

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Lithium has been the standard pharmacological treatment for bipolar disorder over the last 50 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. We characterized the phenotype of mice with a dysfunctional IMPA1 gene (IMPA1 À/À ) to study the in vivo physiological functions of IMPA1, in general, and more specifically its potential role as a molecular target in mediating lithium-dependent physiological effects. Homozygote IMPA1 À/À mice died in utero between days 9.5 and 10.5 post coitum (p.c.) demonstrating the importance of IMPA1 in early embryonic development. Intriguingly, the embryonic lethality could be reversed by myo-inositol supplementation via the pregnant mothers. In brains of adult IMPA1 À/À mice, IMPase activity levels were found to be reduced (up to 65% in hippocampus); however, inositol levels were not found to be altered. Behavioral analysis of the IMPA1 À/À mice indicated an increased motor activity in both the open-field test and the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures, the latter supporting the idea that IMPA1 represents a physiologically relevant target for lithium. In conclusion the IMPA1 À/À mouse represents a novel model to study inositol homeostasis, and indicates that genetic inactivation of IMPA1 can mimic some actions of lithium.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IMPA1 is Essential for Embryonic Development and Lithium-Like Pilocarpine Sensitivity

Cryns¹,

Shamir

Acker

et al. 2007

Neuropsychopharmacol

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“…One 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 pilocarpine alone (Sherman et al 1985a(Sherman et al , 1986.…”

Section: Inositol Reverses Li-pilocarpine Seizuresmentioning

confidence: 99%

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

Belmaker

Agam

Calker

et al. 1998

Neuropsychopharmacology

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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...

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“…Lithium (3mEq/kg) is injected in the rats 24 hours prior to pilocarpine injection. No seizures are produced if the interval of injecting lithium and pilocarpine is more than 48 hours (Honchar, Olney et al 1983). …”

Section: Pilocarpine Model Of Epilepsymentioning

confidence: 99%

“…Injecting lithium results in the requirement of much lower dose of pilocarpine (30mg/kg) for seizure generation (Honchar, Olney et al 1983;Curia, Longo et al 2008). The behavioral features of the rodents are characterized by "salivation, piloerection, tremor, chromodacryorrhea (bloody tears) and diarrhea" after five minutes of pilocarpine injection (Honchar, Olney et al 1983).…”

Section: Pilocarpine Model Of Epilepsymentioning

confidence: 99%

Silencing Hyper-Excitable Neurons as a Treatment for Status Epilepticus and Temporal Lobe Epilepsy.

Dey¹

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Systemic Cholinergic Agents Induce Seizures and Brain Damage in Lithium-Treated Rats

Cited by 345 publications

References 32 publications

IMPA1 is Essential for Embryonic Development and Lithium-Like Pilocarpine Sensitivity

IMPA1 is Essential for Embryonic Development and Lithium-Like Pilocarpine Sensitivity

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

Silencing Hyper-Excitable Neurons as a Treatment for Status Epilepticus and Temporal Lobe Epilepsy.

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