Lithium- and Valproate-Induced Alterations in Circadian Locomotor Behavior in Drosophila

Department of Psychiatry, Washington University in St. Louis, San Luis, Missouri, United States
Neuropsychopharmacology (Impact Factor: 7.05). 01/2006; 30(12):2216-24. DOI: 10.1038/sj.npp.1300764
Source: PubMed


Lithium and valproate are commonly used mood stabilizers, but their action pathways are not clearly understood. They also suffer from multiple toxic effects that limit their utility. Elucidating their action mechanisms could lead to newer agents and better understanding of the etiopathogenesis of bipolar disorder. We have expanded the study of signaling mechanisms of lithium and valproate by using Drosophila circadian locomotor activity as a robust behavioral assay that is amenable to genetic manipulations. We demonstrate that lithium affects the circadian system of Drosophila similarly to what has been reported in the mammalian studies. We show that lithium and valproate share effects on the circadian locomotor activity of Drosophila: they lengthen the period of circadian rhythms and increase arrhythmicity. Valproate exerts these effects in a weaker fashion than does lithium. We also tested the circadian alterations in multiple mutant lines of Drosophila bearing defects in the GSK-3beta gene and other clock genes in response to lithium administration. We show that lithium partially rescues the shortening of circadian period when the GSK-3beta gene is overexpressed only in specific circadian pacemaker neurons, thus implicating GSK-3beta as a component in lithium's effect on the circadian oscillator. Moreover, lithium also lengthens the period in GSK-3beta heterozygous mutants and doubletime long mutants. These results establish a basis for using Drosophila genetics to investigate more fully lithium and valproate action mechanisms.

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Available from: Mehmet E. Dokucu, Feb 03, 2015
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    • "These lithium concentrations were initially chosen based on the paper by Dokucu et al. (2005)—they showed that lithium concentrations ranging from 10 to 100 mM lithium in the fly food translates to roughly 0.05–0.4 mM in the fly tissue (Dokucu et al., 2005), so well below the toxic levels in patients and mice (Wood et al., 1986; Schou, 2001; Can et al., 2011). "
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    • "Data on prescribed psychotropic treatments were recorded for BD cases (none of the HC was being prescribed these medications). This was considered relevant as it is known for example that lithium and valproate lengthen the circadian period [7] [37] and reduce melatonin light sensitivity [10] [11]. Similarly, benzodiazepines and antipsychotics are known to have sedative effects and could act as confounders in this study. "

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    • "This did not have an effect on overall melatonin secretion or the dim-light melatonin onset time [87]. A study evaluating the circadian effects of valproate on Drosophilia found that the drug lengthened the period of the circadian rhythm and promoted rhythmicity [88]. Real-time PCR analysis on mice and human fibroblasts has shown that the valproate can advance or delay the rhythmic expression of the circadian gene Period2::Luciferace depending on the time of administration [89]. "
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