Repeated fentanyl administration impairs spatial memory, synaptic plasticity, and induces neuroinflammation in the...

Repeated opioid exposure, including therapeutic or illicit fentanyl (Fnt) use, disrupts the hippocampal network activity that supports learning and memory. However, the cellular mechanisms underlying these effects remain elusive. To elucidate how Fnt alters hippocampal-dependent behavior, synaptic physiology, and neuroinflammation in the dorsal hippocampus, we conducted behavioral testing, electrophysiological recordings, and immunofluorescence analyses for GFAP, CD11b, and the inflammasome NLPR3 in rats repeatedly administered with Fnt (0.1 mg/kg, three times daily for 7 days; 19 injections). At the end of the administration protocol, Fnt reduced the exploration of relocated objects in the object location task, indicating impaired spatial memory. Extracellular recordings in acute brain slices of the dorsal hippocampus revealed that Fnt decreased the population spike amplitude of CA1 pyramidal cells, the fiber volley-fEPSP synchronization ratio, and altered the paired-pulse facilitation of glutamatergic transmission. Consistent with these findings, the magnitude of long-term potentiation (LTP) induced by theta-burst stimulation was reduced, mirroring decreased synaptic plasticity. Immunoreactivity analyses revealed increased GFAP and CD11b expression, accompanied by microglial hypertrophy and elevated NLRP3 expression in neurons and interneurons in area CA1, indicating astrogliosis and inflammasome priming. These findings indicate that repeated Fnt administration disrupts neuronal and glial homeostasis in the hippocampus.