Venlafaxine Upregulates Cortical Catechol-O-methyltransferase Expression and Activity in Rats and Mice

Clinical trials have demonstrated that venlafaxine affects brain functions in healthy subjects, but its underlying mechanisms remain unclear. The objective of this study was to systematically evaluate the effects of venlafaxine on the expression and activity of catechol-O-methyltransferase (COMT) in cortex of nondepressed rats and mice. Chronic in vivo exposure to venlafaxine for 8 days led to increases in cerebral COMT expression and activity, decreases in the methyl donor S-adenosylmethionine (SAM) levels, downregulation of H3K4me3 and H3K27me3 expression, and alterations in locomotor and exploration activities. Data from U251 cells and primary astrocytes showed that venlafaxine significantly upregulated COMT, p-AKT, p-P70S6K, and p-4EBP1 expression and decreased cellular SAM levels. Phosphatidylinositol 3-kinase inhibitor LY294002, mammalian target of rapamycin inhibitor rapamycin, silencing P70S6K, or silencing 4EBP1 remarkably attenuated venlafaxine-induced upregulation of COMT. Rapamycin or silencing P70S6K and 4EBP1 reversed venlafaxine-mediated deficiency of cellular SAM levels. In mice, rapamycin significantly attenuated venlafaxine-induced increases in cortical expression of COMT, p-P70S6K, and p-4EBP1, decreases in cortical SAM levels and locomotor and exploration activities, and downregulations of H3K4me3 and H3K27me3 expression. Furthermore, COMT inhibitor tolcapone reversed venlafaxine-induced decreases in SAM levels, H3K4me3 and H3K27me3 expression, and locomotor and exploration activities. Supplementing SAM also remarkably attenuated venlafaxine-induced decreases in H3K4me3 and H3K27me3 expression and behavioral alterations. These observations were further confirmed in U251 cells and primary astrocytes. These results indicate that venlafaxine induces cortical COMT via phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway to decreasing SAM levels. Depletion of cortical SAM levels partly contributes to the decreases in activities of locomotor and exploration and expression of H3K4me3 and H3K27me3. SIGNIFICANCE STATEMENT: This study revealed that venlafaxine upregulated cortical catechol-O-methyltransferase expression and activity via activating phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway. The induction of catechol-O-methyltransferase led to depletion of cortical S-adenosylmethionine, which may partly contribute to the decreases in locomotor and exploration activities and downregulations of H3K4me3 and H3K27me3 expression in cortex of rats and mice.