Astrocytic Disruption and Cognitive Impairment Following Sub-Acute Fentanyl Administration in Male Rats Publisher



Dolatshahi S ; Omran HS ; Beirami A ; Hasanzadeh M ; Zeynalzadeh A ; Parvardeh S ; Ashtari S ; Abianeh PR ; Shirvani P ; Shirvani P ; Moteshakereh SM ; Navaei F ; Bayat AH ; Sani M Show All Authors
Source: 3 Biotech Published:2026

Abstract

Fentanyl is a potent, fast-acting synthetic opioid that has played a major role in the opioid overdose crisis in the United States for over five decades, with opioid-related deaths increasing sharply in recent years. This study investigates the behavioral, histological, and molecular changes in the hippocampus of rats subjected to sub-acute fentanyl exposure. Two groups of rats were studied: one group received multiple fentanyl injections over approximately one week, while the control group received no fentanyl. A battery of behavioral tests related to memory and depression—including the Y-maze, shuttle box, tail suspension test, elevated plus maze, Barnes maze, Morris water maze, and forced swimming test—was administered. Electrophysiological assessments, including field potential recording and electromyography (EMG), were conducted to evaluate neural activity. Western blot analysis was performed to quantify the expression of brain-derived neurotrophic factor (BDNF) and RE1-silencing transcription factor (REST), while immunohistochemical analyses assessed hippocampal cellular alterations. Results showed that sub-acute fentanyl administration impaired behavioral performance in memory assessment tests (Y maze (P < 0.05), shuttle box (P < 0.01)). However, fentanyl did not alter spatial memory assessed by Morris water maze and Barnes maze relative to controls. Moreover, LTP was decreased in fentanyl group compared to the control group (P < 0.01). Locomotor activity (P < 0.05) and EMG latency (P < 0.01) were also diminished following fentanyl exposure. Notably, increased astrogliosis (P < 0.01) and astrocyte reactivity (P < 0.001) were observed, indicating significant disruptions in astrocyte neurobiology. Furthermore, BDNF expression was reduced (P < 0.001), whereas REST expression was elevated (P < 0.001) in the fentanyl-treated group. These findings offer initial insights into the neurobiological effects of fentanyl, underscoring the potential role of astrocytes in fentanyl-induced cognitive dysfunction and the broader implications for memory-related neuroregeneration. © King Abdulaziz City for Science and Technology 2026.