Abstract
The number of drug overdose deaths involving opioids continues to rise in the United States. Many patients with opioid use disorder (OUD) that seek treatment still experience relapse. Perseverant opioid seeking behaviors represent a major challenge to treating OUD and additional therapeutic development will require insight into opioid-induced neurobiological adaptations. In this study, we explored the regulation of a novel class of RNAs, circular RNAs (circRNAs), by the addictive opioid heroin in the rat orbitofrontal cortex (OFC), a brain region that mediates behavioral responses to rewarding stimuli. Microarray analysis identified 76 OFC circRNAs significantly regulated in male rats after heroin self-administration. We evaluated the specificity of these findings by measuring heroin-associated circRNA expression in female rats after heroin self-administration and in rats that self-administered sucrose. We identify circGrin2b, circUbe2cp, circAnks1a, circAdcy5 and circSlc24A2 as heroin-responsive circRNAs in the OFC. Linear mRNA levels of heroin-associated circRNAs were unchanged except for Grin2b and Adcy5. An integrated bioinformatics analysis of regulated circRNAs identified microRNAs predicted to bind heroin-associated circRNAs and downstream targets of circRNA: microRNA sponging. Thus, heroin regulates the expression of OFC RNA splice variants that circularize and may impact cellular processes that contribute to the neurobiological adaptations that arise from chronic heroin exposure.
Highlights
Opioid overdose and deaths continue to rise in the United States, where nearly 190 people die every day from opioid intoxication [1]
To address this crucial issue, this study explored expression patterns of a novel class of RNA, circular RNAs, that are regulated in response to self-administration of the opioid heroin in a rat model of drug seeking
To identify brain circRNAs regulated by heroin exposure, we performed an unbiased circRNA expression analysis on orbitofrontal cortex (OFC) tissue from rats that underwent heroin selfadministration (Figure 1)
Summary
Opioid overdose and deaths continue to rise in the United States, where nearly 190 people die every day from opioid intoxication [1]. Understanding the cellular and molecular pathways dysregulated by opioid exposure will provide insight into non-mu-opioid receptor targets that may be identified for more comprehensive treatment of OUD. To address this crucial issue, this study explored expression patterns of a novel class of RNA, circular RNAs (circRNAs), that are regulated in response to self-administration of the opioid heroin in a rat model of drug seeking. Exploration of circRNAs in opioid exposure models provides a unique body of information that may inform substance abuse researchers of entirely unknown molecular signaling cascades associated with the critically complex and important phenotypes of opioid seeking
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