• Payman Raise-Abdullahi, Mehrnoush Rahmani, Narges Sadat Tabaei, Fatemeh Rezamohammadi, Abbas Ali Vafaei, Ali Ghanbari, Hamed Rashidipour, Morvarid Meamar, and Ali Rashidy-Pour.
• Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran.
• Neuroscience. 2025 Feb 16; 567: 209218209-218.

AbstractCorticosteroid signaling plays a critical role in modulating the neural systems underlying reward and addiction, but the specific contributions of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in the medial prefrontal cortex (mPFC) to opioid reward and dopaminergic plasticity remain unclear. Here, we investigated the effects of intra-mPFC injection of corticosteroid receptor ligand (corticosterone; CORT), glucocorticoid receptor antagonist (RU38486; RU), and mineralocorticoid receptor antagonist (spironolactone; SP) on morphine-induced conditioned place preference (CPP) and dopamine transporter (DAT) expression in the mPFC. Adult male Wistar rats received intra-mPFC injections of CORT, RU, SP, or their respective vehicles prior to morphine CPP conditioning. Blockade of GRs with RU (10 or 100 ng) or MRs with a low dose of SP (10 ng) attenuated the expression of morphine CPP. Morphine reduced DAT expression in the mPFC, but RU and SP prevented this effect. These findings demonstrate that corticosteroid receptor signaling within the mPFC modulates the rewarding properties of morphine and morphine-induced dopaminergic plasticity. This preclinical study suggests that targeting GRs and MRs in the mPFC could be a possible therapeutic approach for treating opioid addiction. By targeting these receptors, it may be possible to reduce opioid reward and counteract the neuroadaptations in dopamine systems associated with addiction.Copyright © 2025 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.

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