DNMT3a in the hippocampal CA1 is crucial in the acquisition of morphine self-administration in rats.

Drug-reinforced excessive operant responding is one fundamental feature of long-lasting addiction-like behaviors and relapse in animals. However, the transcriptional regulatory mechanisms responsible for the persistent drug-specific (not natural rewards) operant behavior are not entirely clear. In this study, we demonstrate a key role for one of the de novo DNA methyltransferase, DNMT3a, in the acquisition of morphine self-administration (SA) in rats. The expression of DNMT3a in the hippocampal CA1 region but not in the nucleus accumbens shell was significantly up-regulated after 1- and 7-day morphine SA (0.3 mg/kg/infusion) but not after the yoked morphine injection. On the other hand, saccharin SA did not affect the expression of DNMT3a or DNMT3b. DNMT inhibitor 5-aza-2-deoxycytidine (5-aza) microinjected into the hippocampal CA1 significantly attenuated the acquisition of morphine SA. Knockdown of DNMT3a also impaired the ability to acquire the morphine SA. Overall, these findings suggest that DNMT3a in the hippocampus plays an important role in the acquisition of morphine SA and may be a valid target to prevent the development of morphine addiction.

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