MicroRNA-132/212 negatively modulates opioid reward by targeting dopamine transporter in the ventral tegmental area

Addictive drugs, notably opioid drugs, have significant societal implications, yet the cellular and molecular mechanisms underpinning rewarding effects remain largely elusive. Noncoding transcripts, including the microRNAs (miRNAs), are pivotal regulators of diverse biological functions. Notably, the microRNAs miR-132 and miR-212, arising from a shared noncoding transcript, have links to several psychiatric conditions, including cocaine addiction. However, their contribution to opiate rewarding remains speculative. In this study, we discovered that repeated morphine administration decreases the expression of miR-132/212 in the ventral tegmental area (VTA) and induces a concurrent upregulation of the dopamine transporter (DAT). Using a luciferase reporter assay, we found that the DAT coding gene, SLC6A3 mRNA 3'UTR, is a direct target of miR-132/212. These miRNAs negatively regulated both mRNA expression and protein levels of DAT in vitro. This was corroborated by in vivo studies which revealed that behavioral experiments using a morphine-induced conditioned place preference (CPP) paradigm showed that suppression of miR-132/212 in the VTA facilitated the formation of morphine-induced CPP. Conversely, overexpression of miR-132 attenuated morphine preference in male and female adult rats, as well as adolescents. In sum, our findings uncover a regulatory mechanism wherein miR-132/212 modulates morphine induced reward behavior by fine-tuning DAT expression at the posttranscriptional level, providing a potential therapeutic target of rewarding effects.