Methylation in Syn and Psd95 genes underlie the inhibitory effect of oxytocin on oxycodone-induced conditioned place...

Oxycodone (Oxy) is one of the most effective analgesics in medicine, but is associated with the development of dependence. Recent studies demonstrating epigenetic changes in the brain after exposure to opiates have provided an insight into possible mechanisms underlying addiction. Oxytocin (OT), an endogenous neuropeptide well known for preventing drug abuse, is a promising pharmacotherapy to counteract addiction. Therefore, we explored the mechanism of Oxy addiction and the role of OT in Oxy-induced epigenetic alterations. In this study, drug-induced changes in conditioned place preference (CPP), i.e. the expression of synaptic proteins and synaptic density in the ventral tegmental area (VTA) were measured. We also sought to identify DNA methyltransferases (DNMTs), ten-eleven translocations (TETs), global 5-methylcytosine (5-mC), and DNA methylation of two genes implicated in plasticity (Synaptophysin, Syn; Post-synaptic density protein 95, Psd95). Oxy (3.0 mg/kg, i.p.) induced CPP acquisition in Sprague-Dawley rats. Oxy down-regulated DNMT1 and up-regulated TET1-3, leading to a decrease in global 5-mC levels and differential demethylation at exon 1 of Syn and exon 2 of Psd95. These changes in DNA methylation of Syn and Psd95 elevated the expression of synaptic proteins (SYN, PSD95) and synaptic density in the VTA. Pretreatment with OT (2.5 µg, i.c.v.) via its receptor specifically blocked Oxy CPP, normalized synaptic density, and regulated DNMT1 and TET2-3 causing reverse of DNA demethylation of Syn and Psd95. DNA methylation is an important gene regulation mechanism underlying Oxy CPP, and OT - via its receptor - could specifically inhibit Oxy addiction.