ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Neuropharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1653356
This article is part of the Research TopicNovel Therapeutic Strategies for SUD: Beyond Traditional ApproachesView all articles
Escalated oxycodone self-administration is associated with expression of voltage gated and calcium activated potassium channels in the mesocorticolimbic system in rats
Provisionally accepted
- 1National Institute on Drug Abuse Intramural Research Program, Baltimore, United States
- 2National Institutes of Health (NIH), Bethesda, United States
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Background: The number of individuals diagnosed with opioid use disorder (OUD) has risen steeply because of increased prescribing of opioid drugs including oxycodone for chronic pain relief. When rats given extended access to oxycodone only a subset of animals self-administers more drug over time. Identifying the molecular mechanism associated with this behavior can introduce novel ways to combat OUD. Herein, we sought to identify the alteration in the expression of voltage gated and calcium activated potassium channels after extended access to oxycodone self-administration. Methods: We used male Sprague-Dawley rats that self-administered oxycodone for 20 days according to short-access (ShA, 3 hours per day) and long-access (LgA, 9 hours per day) paradigms. Results: LgA rats escalated their oxycodone intake and developed into 2 phenotypes, named long-access high (LgA-H, escalated intake) and long-access low (LgA-L, non-escalated intake) rats, based on the quantities of oxycodone intake during the self-administration experiment. ShA rats maintained similar oxycodone intake throughout 20 days of self-administration. Rats were euthanized 2 hours after the last self-administration session and their prefrontal cortex (PFC), nucleus accumbens (NAc), and hippocampus (HIP) were dissected out for gene expression analysis. Given the relationship between potassium channels and substance use disorder we performed gene expression analysis for voltage and calcium activated potassium channels. The expression of potassium channels in oxycodone self-administered rats was found to be brain region dependent. Specifically, LgA-H rats displayed increased expression of Kcnd2, Kcnd3, Kcng2 and Kcnt1 in their NAc. In the PFC, LgA-L group showed higher mRNA levels for Kcna3, Kcna4, Kcnd3, Kcnq4, Kcnq5, Kcnma1 and Kcnn2. Finally, Kcna5, Kcna10, Kcng1, Kcnn1 and Kcnn2 found to be upregulated in the HIP of ShA rats. Conclusion: Our observation is of significant translational importance providing further support that targeting potassium channel can lead to development of better therapeutic approaches against OUD in humans.
Keywords: Oxycodone, Potassium Channels, mRNA, Prefrontal Cortex, Nucleus Accumbens, Hippocampus, self-administration
Received: 24 Jun 2025; Accepted: 30 Jul 2025.
Copyright: © 2025 Wabreha, Adjei, Ladenheim, Cadet and Daiwile. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Atul P Daiwile, National Institutes of Health (NIH), Bethesda, United States
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