The antibipolar drug valproate mimics lithium in stimulating glutamate release and inositol 1,4,5-trisphosphate accumulation in brain cortex slices but not accumulation of inositol monophosphates and bisphosphates

Dixon, John F.; Hokin, Lowell E.

doi:10.1073/pnas.94.9.4757

Cited by 67 publications

(45 citation statements)

References 21 publications

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“…As described in the Materials and Methods section, the CA 3 pyramidal neurons are activated by quisqualate, hence, it is important to mention that lithium can also affect glutamate neurotransmission. In fact, it has been shown that lithium blocks the uptake of glutamate from cerebral cortex slices of monkey and mouse (Dixon et al 1994;Dixon and Hokin 1997). Moreover in the , rats treated with imipramine for 21 days (10 mg/kg/ day, SC, IMI), rats treated with imipramine and having a lithium diet (IMI ϩ Li ϩ ), rats treated with tranylcypromine for 21 days (2.5 mg/kg/day, SC, TCP), rats treated with tranylcypromine and having a lithium diet (TCP ϩ Li ϩ ), rats treated with paroxetine for 21 days (10 mg/kg/day, SC, PRX) and rats treated with paroxetine and having a lithium diet (PRX ϩ Li ϩ ).…”

Section: Discussionmentioning

confidence: 99%

Increased Tonic Activation of Rat Forebrain 5-HT1A Receptors by Lithium Addition to Antidepressant Treatments

Haddjeri

Szabo

Montigny

et al. 2000

Neuropsychopharmacology

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The present study was undertaken to determine whether lithium addition to long-term treatment with different classes of antidepressant drugs could induce a greater effect on the serotonin (5-HT) system than the drugs given alone. Because 5-HTAlthough the physiopathology of major depression is not fully defined, there is a growing body of evidence suggesting the implication of the serotonin (5-HT) system in the therapeutic effect of antidepressant treatments (Heninger and Charney 1987;Price et al. 1990a;Van Praag et al. 1990;Cummings 1993;Blier and de Montigny 1994;Maes and Meltzer 1995). For example, it has been shown that long-term tricyclic antidepressant (TCA) treatment and repeated electroconvulsive shock (ECS) administration lead to enhanced 5-HT neurotransmission via sensitization of the postsynaptic 5-HT 1A receptors (de Montigny and Aghajanian 1978;de Montigny 1984;Welner et al. 1989;Nowak and Dulinski 1991;Stockmeier et al. 1992). Long-term treatment with either monoamine oxidase inhibitors (MAOIs) or selective 5-HT reuptake inhibitors (SSRIs) results in a desensitization of the somatodendritic 5-HT 1A autoreceptor of 5-HT neurons in the dorsal raphe nucleus, thereby allowing their firing rate to recover in Received May 14, 1999; revised October 18, 1999; accepted October 19, 1999. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 22 , NO . 4 5-HT Transmission and Lithium Addition 347 the presence of the drugs Chaput et al. 1986). In addition, long-term SSRI treatment also desensitizes terminal 5-HT 1B autoreceptors; whereas, longterm MAOI treatment desensitizes terminal ␣ 2 -adrenergic heteroreceptors located on 5-HT terminals (Blier and Bouchard 1994;Mongeau et al. 1994). The desensitization of the latter two receptors is thought to contribute to a greater release of 5-HT following SSRI and MAOI administration. Long-term treatment with the antidepressant mirtazapine, an ␣ 2 -adrenoceptor antagonist, increases 5-HT neurotransmission as a result of a sustained increase in the firing activity of 5-HT neurons in the presence of the decreased function of ␣ 2 -adrenergic heteroreceptors located on 5-HT terminals ). Finally, long-term treatment with 5-HT 1A receptor agonists, such as gepirone, desensitizes the 5-HT 1A autoreceptor on 5-HT neurons, but not the postsynaptic 5-HT 1A receptors located on CA 3 pyramidal neurons .Recently, novel direct evidence of an enhanced 5-HT neurotransmission by antidepressant treatments has been provided (Haddjeri et al. 1998a). This study showed that long-term treatment with either the TCA imipramine, the SSRI paroxetine, the selective and reversible MAO-A inhbitor befloxatone, the ␣ 2 -adrenergic antagonist mirtazapine, the 5-HT 1A receptor agonist gepirone, as well as repeated ECS administration, enhanced the tonic activation of postsynaptic 5-HT 1A receptors in the dorsal hippocampus, as put into evidence by the enhanced disinhibition produced by the acute administration of the selective 5-HT 1A receptor antagonist WAY 100635 (Haddjeri et al. 1998a). Furthermore, no disinhibi...

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Section: Discussionmentioning

confidence: 99%

Increased Tonic Activation of Rat Forebrain 5-HT1A Receptors by Lithium Addition to Antidepressant Treatments

Haddjeri

Szabo

Montigny

et al. 2000

Neuropsychopharmacology

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“…Previous studies indicated that valproate does not inhibit bovine brain (16) or yeast inositol monophosphatase activity (17) and has a minimal effect on receptor-mediated phosphoinositide turnover (18). In addition, valproate does not lead to large accumulations of inositol mono-or bisphosphates, as seen with lithium (19).…”

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confidence: 96%

“…Inhibition of this reaction by valproate is further supported by the observation that the opi1 mutant does not exhibit increased resistance to valproate, despite constitutive expression of INO1 and increased levels of Ins-1-P synthase (30). Previous findings that valproate does not inhibit inositol monophosphatase or cause an accumulation of inositol phosphates (16,19) have been cited as evidence against the inositol-depletion hypothesis. The experiments shown in this report indicate that valproate does indeed cause inositol depletion.…”

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confidence: 99%

Lithium and Valproate Decrease Inositol Mass and Increase Expression of the Yeast INO1 and INO2Genes for Inositol Biosynthesis

Vaden¹,

Ding²,

Peterson

et al. 2001

Journal of Biological Chemistry

115

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Bipolar affective disorder (manic-depressive illness)is a chronic, severe, debilitating illness affecting 1-2% of the population. The Food and Drug Administration-approved drugs lithium and valproate are not completely effective in the treatment of this disorder, and the mechanisms underlying their therapeutic effects have not been established. We are employing genetic and molecular approaches to identify common targets of lithium and valproate in the yeast Saccharomyces cerevisiae. We show that both drugs affect molecular targets in the inositol metabolic pathway. Lithium and valproate cause a decrease in intracellular myo-inositol mass and an increase in expression of both a structural (INO1) and a regulatory (INO2) gene required for inositol biosynthesis. The opi1 mutant, which exhibits constitutive expression of INO1, is more resistant to inhibition of growth by lithium but not by valproate, suggesting that valproate may inhibit the Ino1p-catalyzed synthesis of inositol 1-phosphate. Consistent with this possibility, growth in valproate leads to decreased synthesis of inositol monophosphate. Thus, both lithium and valproate perturb regulation of the inositol biosynthetic pathway, albeit via different mechanisms. This is the first demonstration of increased expression of genes in the inositol biosynthetic pathway by both lithium and valproate. Because inositol is a key regulator of many cellular processes, the effects of lithium and valproate on inositol synthesis have far-reaching implications for predicting genetic determinants of responsiveness and resistance to these agents.Bipolar disorder, or manic-depressive illness, is a common condition with a lifetime prevalence of 1-2% (1). It is characterized by recurring bouts of mania and depression, which have deleterious effects on career and interpersonal relationships. Approximately 15% of those afflicted commit suicide, and mortality rates because of physical disorders are also increased (2, 3). For decades, lithium has been the most effective agent for the treatment of bipolar illness (4). Despite the marked benefit that many patients obtain from lithium therapy, 20 -40% of patients fail to show a satisfactory antimanic response to lithium, and many patients suffer significant morbidity (5). More recently, the branched fatty acid valproate has been used for treatment of bipolar disorder (6). Like lithium, it is not completely effective, and the molecular mechanisms underlying its therapeutic effects have not been elucidated. Lithium and valproate exert a variety of biochemical effects, only some of which are likely to be related to their therapeutic mechanisms of action. Identifying common targets of lithium and valproate is an approach that may more directly address the therapeutic mechanisms underlying their efficacy (7-11).The inositol depletion hypothesis proposes that lithium acts by depletion of inositol from the brain. This is based on the observed uncompetitive inhibition of inositol monophosphatases by lithium, resulting in decreased inositol, an i...

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“…Furthermore, lithium and VPA can down-regulate expression of protein kinase C isoforms PKC␣ and PKC⑀, induce expression of the anti-apoptotic gene bcl-2, and activate AP-1-dependent transcription (through a direct effect on c-jun activity and by increasing expression of c-Jun (11,12)). Both VPA and lithium also stimulate glutamate release and inositol 1,4,5-trisphosphate accumulation in mouse cerebral cortex slices, although apparently through distinct mechanisms (14). Furthermore, both VPA and lithium have been shown to confer protection from neurotoxic agents (15)(16)(17).…”

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confidence: 99%

Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen

Phiel¹,

Zhang²,

Huang³

et al. 2001

Journal of Biological Chemistry

1,579

1,194

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Valproic acid is widely used to treat epilepsy and bipolar disorder and is also a potent teratogen, but its mechanisms of action in any of these settings are unknown. We report that valproic acid activates Wntdependent gene expression, similar to lithium, the mainstay of therapy for bipolar disorder. Valproic acid, however, acts through a distinct pathway that involves direct inhibition of histone deacetylase (IC 50 for HDAC1 ‫؍‬ 0.4 mM). At therapeutic levels, valproic acid mimics the histone deacetylase inhibitor trichostatin A, causing hyperacetylation of histones in cultured cells. Valproic acid, like trichostatin A, also activates transcription from diverse exogenous and endogenous promoters. Furthermore, valproic acid and trichostatin A have remarkably similar teratogenic effects in vertebrate embryos, while non-teratogenic analogues of valproic acid do not inhibit histone deacetylase and do not activate transcription. Based on these observations, we propose that inhibition of histone deacetylase provides a mechanism for valproic acid-induced birth defects and could also explain the efficacy of valproic acid in the treatment of bipolar disorder.

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The antibipolar drug valproate mimics lithium in stimulating glutamate release and inositol 1,4,5-trisphosphate accumulation in brain cortex slices but not accumulation of inositol monophosphates and bisphosphates

Cited by 67 publications

References 21 publications

Increased Tonic Activation of Rat Forebrain 5-HT1A Receptors by Lithium Addition to Antidepressant Treatments

Increased Tonic Activation of Rat Forebrain 5-HT1A Receptors by Lithium Addition to Antidepressant Treatments

Lithium and Valproate Decrease Inositol Mass and Increase Expression of the Yeast INO1 and INO2Genes for Inositol Biosynthesis

Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen

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