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A common mechanism of action for three mood-stabilizing drugs

Abstract

Lithium, carbamazepine and valproic acid are effective mood-stabilizing treatments for bipolar affective disorder. The molecular mechanisms underlying the actions of these drugs and the illness itself are unknown. Berridge and colleagues1 suggested that inositol depletion may be the way that lithium works in bipolar affective disorder, but others have suggested that glycogen synthase kinase2,3 (GSK3) may be the relevant target. The action of valproic acid has been linked to both inositol depletion4,5 and to inhibition of histone deacetylase6 (HDAC). We show here that all three drugs inhibit the collapse of sensory neuron growth cones and increase growth cone area. These effects do not depend on GSK3 or HDAC inhibition. Inositol, however, reverses the effects of the drugs on growth cones, thus implicating inositol depletion in their action. Moreover, the development of Dictyostelium is sensitive to lithium7 and to valproic acid, but resistance to both is conferred by deletion of the gene that codes for prolyl oligopeptidase, which also regulates inositol metabolism. Inhibitors of prolyl oligopeptidase reverse the effects of all three drugs on sensory neuron growth cone area and collapse. These results suggest a molecular basis for both bipolar affective disorder and its treatment.

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Acknowledgements

This study was an equal collaboration between the Harwood and Mudge research groups, and the paper was co-written by A.W.M. and A.J.H. The neuron experiments were carried out by L.C., and Dictyostelium experiments by R.S.B.W. and A.J.H. The neuron analysis was designed by A.W.M., and carried out by R.S.B.W. and A.W.M. The work was supported by both MRC (L.C., A.W.M.) and Wellcome Trust funding (A.J.H. and R.S.B.W.). We thank L. Cramer for discussions. We also thank M. Shipman and B. Mudge for help with microscopy and graphics, respectively.

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Correspondence to Anne W. Mudge.

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The authors declare that they have no competing financial interests.

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Figure 1: Structural changes in sensory neuron axons following treatment with mood-stabilizing drugs.
Figure 2: Inositol reverses the effects of mood-stabilizing drugs on growth cone collapse and spread area.
Figure 3: VPA effects on Dictyostelium aggregation are due to modulation of InsP3 signalling.
Figure 4: Inhibitors of prolyl oligopeptidase enzyme activity block the action of mood-stabilizing drugs on growth cone collapse and spread area.

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