Neural transcriptomic and epitranscriptomic modifications by fentanyl and xylazine

Biography

Benjamin Reiner earned a PhD in Pharmacology and Experimental Neuroscience from the University of Nebraska Medical Center and completed his Postdoctoral Fellowship in the Department of Psychiatry at the University of Pennsylvania Perelman School of Medicine. Now a Research Assistant Professor in the same department, his laboratory focuses on using behavioural, pharmacological, and intersectional genetic approaches with neural multiomics and downstream bioinformatics in preclinical animal models of psychiatric disease, substance use disorders, and diseases of feeding and energy balance.

Abstract

Use of fentanyl, a potent synthetic opioid, combined with xylazine, a veterinary sedative increasingly found in human drug supplies, represents a major public health concern. While their individual effects on behavior and physiology are well documented, limited information is available on their combined effects on the brain at the molecular level. This study employed direct RNA sequencing to characterize transcriptomic and epitranscriptomic modifications in the nucleus accumbens of rats following self-administration of fentanyl, xylazine, fentanyl and xylazine, or vehicle. Direct RNA sequencing offers the advantage of capturing full-length transcripts and RNA modifications, providing insights into both gene expression and RNA processing dynamics. Behavioral observations confirmed drug self-administration, with differences in intake observed across drug conditions. Transcriptomic analyses revealed significant gene and isoform expression alterations, while epitranscriptomic profiling identified alterations in RNA modifications associated with drug exposure. These findings shed light on the molecular underpinnings of fentanyl and xylazine's effects on the reward system, highlighting distinct and overlapping mechanisms. This study provides a foundation for understanding how these substances, alone or in combination, alter brain function, which may inform strategies for mitigating their addictive potential and neurotoxic effects.