Epigenetic induction of melatonin MT₁ receptors by valproate: Neurotherapeutic implications

We have reported that the anticonvulsant/mood stabilizer and histone deacetylase (HDAC) inhibitor valproate (VPA) induces expression of melatonin receptors both in vitro and in vivo, but the mechanisms involved were not known. Here we show that pharmacological inhibition of CREB, PKC, PI3K, or GSK3β signaling pathways, which are known targets for VPA, do not prevent its upregulation of melatonin MT₁ receptors in rat C6 glioma cells. M344, an HDAC inhibitor unrelated to VPA, mimics the effects of VPA on MT₁ expression, whereas valpromide, a VPA derivative lacking HDAC inhibitory activity, does not. Furthermore, VPA, at a concentration which upregulates the MT₁ receptor, induces histone H3 hyperacetylation along the length of the MT₁ receptor promoter. These results show that an epigenetic mechanism involving histone acetylation underlies induction of MT₁ receptor expression by VPA. Given the neuropsychiatric effects of melatonin coupled with evidence that VPA upregulates melatonin receptors in the rat brain, these findings suggest that the melatonergic system contributes to the psychotropic effects of VPA.