Specificity of mood stabilizer action on neuronal growth cones

Objectives: Lithium, valproic acid (VPA) and carbamazepine (CBZ) are commonly used mood stabilizers, but their therapeutic mechanism is unclear. These drugs all cause the same morphological effects on postnatal rat neuronal dorsal root ganglia (DRG) growth cones via an inositol-reversible mechanism. However, due to limitations in earlier analysis, the effects of combining drugs, drug specificity and inositol stereoisomer specificity are unknown. We devised an improved analytical method to address these issues. Methods: Dorsal root ganglia explants were cultured individually and incubated with combinations of psychotropic drugs and inositol stereoisomers. We recorded axonal growth cone morphology and calculated growth cone area per a modified method described by Williams et al. (Nature 2002; 417: 292-295). Statistically significant changes in area were calculated using non-parametric statistical testing. Results: (i) Lithium and VPA showed an additive effect on growth cone spreading. (ii) Among eight additional psychotropic drugs to those previously tested, only imipramine and chlorpromazine altered DRG growth cone morphology. As this effect was not reversed by myo-inositol, it arises from a different mechanism to the mood stabilizers lithium, VPA and CBZ. (iii) Myo-inositol, but not scyllo- or epi-inositol, causes a significant reversal of the lithium effect on the growth cones spreading, consistent with the inositol depletion hypothesis. Conclusions: These results show that lithium, VPA and CBZ are unique in causing altered neuronal morphology via myo-inositol depletion.