Reversal of oxycodone conditioned place preference by oxytocin: Promoting global DNA methylation in the hippocampus

Repeated exposure to the opioid agonist, oxycodone, can lead to addiction. Accumulating evidence has shown that oxytocin (OT), a neurohypophyseal neuropeptide, could reduce the abuse potential of drugs. Recent studies suggest that epigenetic regulation through DNA methylation are involved in neuroadaptations. The current study was conducted to investigate the effects of OT on oxycodone conditioned place preference (CPP) and the epigenetic mechanism of OT in the hippocampus. For induction of CPP, oxycodone (3.0 mg/kg, i. p.) was administrated to male Sprague-Dawley rats once every other day during an eight-day conditioning phase. Global 5-methylcytosine (5-mC) level was determined based on CPP procedure, including acquisition, expression, extinction and reinstatement. We also measured mRNA levels of DNA methyltransferases (Dnmts), ten-eleven translocations (Tets) and synaptic genes (Psd95, Shank2, Gap43, etc.), and determined synaptic density after restraint stress-induced reinstatement of oxycodone CPP. The results showed that OT (2.5 μg, i. c.v.) pretreatment specifically inhibited the CPP acquisition and expression, facilitated the CPP extinction, and abolished restraint stress-induced reinstatement of oxycodone CPP. OT markedly inhibited global 5-mC changes induced by oxycodone CPP in the four phases. Following restraint stress-induced reinstatement of oxycodone CPP, OT significantly increased mRNA levels of Dnmt1, decreased Tet1 mRNA, synaptic proteins and synaptic density in the hippocampus. Our study indicated that reversal of global DNA hypomethylation through OT could significantly attenuate the rewarding effects induced by oxycodone. Our results suggested that OT could be specific manipulation on oxycodone addiction.