Heroin Regulates Orbitofrontal Circular RNAs

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.

Psilocybin reduces heroin seeking behavior and modulates inflammatory gene expression in the nucleus accumbens and prefrontal cortex of male rats

“…Jugular vein catheter implantation and long-access heroin SA were performed as previously described 33, 34 , in 6-hour (hr) daily sessions on a fixed ratio (FR) 1 schedule at a dose of 0.075 mg/kg/infusion of heroin. Following SA, rats underwent forced abstinence in their home cage for 17 or 21 days (D).…”

MicroRNA-mediated translational pathways are regulated in the orbitofrontal cortex and peripheral blood samples during acute abstinence from heroin self-administration

“…Self-administration of 0.03 mg/kg/infusion heroin and sucrose on an FR1 schedule was performed as previously reported [ 6 , 24 , 33 ]. Self-administration data for heroin animals was previously reported [ 24 ].…”

Molecular and Epigenetic Aspects of Opioid Receptors in Drug Addiction and Pain Management in Sport

“…Arrays were recently used to identify heroin-responsive circRNAs in the rat orbitofrontal cortex, the brain region that mediates behavioral responses to rewarding stimuli. A total of 76 circRNAs resulted differently expressed vs. control rats and the deregulated and validated marks included circAnks1a, circSlc24a2, circGrin2b, circAdcy5 and circUbe2cbp, corresponding to the linear mRNA encoding for ankyrin repeat and sterile alpha motif domain containing 1B, solute carrier family 24 member 2, glutamate ionotropic receptor NMDA type subunit 2B, adenylate cyclase 5 and ubiquitin protein ligase E3D, notably involved in cytoskeleton remodeling, transmembrane transport, cell signaling and cellular protein recycling [151]. CircAdcy5 and circGrin2b, but not circSlc24a2, circAnks1a and circUbe2cbp, were co-regulated with their linear mRNA.…”

“…CircAdcy5 and circGrin2b, but not circSlc24a2, circAnks1a and circUbe2cbp, were co-regulated with their linear mRNA. Target miRNAs downstream of heroin-associated circRNAs were also identified using an integrated bioinformatics approach, thus revealing different mechanisms in the neurobiological adaptations that arise from chronic heroin exposure [151].…”