Methamphetamine Induces TET1- and TET3-Dependent DNA Hydroxymethylation of <italic>Crh</italic> and <italic>Avp</italic> Genes in the Rat Nucleus Accumbens.

Methamphetamine (METH) addiction is a biopsychosocial disorder that is accompanied by multiple relapses even after prolonged abstinence, suggesting the possibilities of long-lasting maladaptive epigenetic changes in the brain. Here, we show that METH administration produced time-dependent increases in the expression of <italic>corticotropin-releasing hormone</italic> (<italic>Crh</italic>/<italic>Crf</italic>), <italic>arginine vasopressin</italic> (<italic>Avp</italic>), and <italic>cocaine- and amphetamine-regulated transcript prepropeptide</italic> (<italic>Cartpt</italic>) mRNAs in the rat nucleus accumbens (NAc). Chromatin immunoprecipitation (ChIP) assays revealed that METH increased the abundance of phosphorylated CREB (pCREB) at the promoter of <italic>Cartpt</italic> but not at <italic>Avp</italic> or <italic>Crh</italic> DNA sequences. In contrast, METH produced DNA hypomethylation at sites near the <italic>Crh</italic> transcription start site (TSS) and at intragenic <italic>Avp</italic> sequences. METH also increased DNA hydroxymethylation at the <italic>Crh</italic> TSS and at intragenic <italic>Avp</italic> sites. In addition, METH increased the protein expression of ten-eleven-translocation enzymes that catalyze DNA hydroxymethylation. Importantly, METH increased TET1 binding at the <italic>Crh</italic> promoter and increased TET3 binding at <italic>Avp</italic> intragenic regions. We further tested the role of TET enzymes in METH-induced changes in gene expression by using the TET inhibitor, 1,5-isoquinolinediol (IQD), and found that IQD blocked METH-induced increases in <italic>Crh</italic> and <italic>Avp</italic> mRNA expression. Together, these results indicate that METH produced changes in neuropeptide transcription by both activation of the cAMP/CREB pathway and stimulation of TET-dependent DNA hydroxymethylation. These results provide molecular evidence for epigenetic controls of METH-induced changes in the expression of neuropeptides. [ABSTRACT FROM AUTHOR]