Transcriptomic characterization of prefrontal cortical remodeling and glutamate changes detected by Glu-CEST MRI in rats with propofol-induced neuroadaptations.

Propofol, a widely used intravenous anesthetic, carries an underrecognized risk of abuse and dependence; however, the prefrontal cortical molecular alterations and in vivo glutamatergic changes associated with propofol-induced neuroadaptations remain poorly characterized. The present study established a rat model of intravenous propofol self-administration (SA) using a fixed-ratio 1 (FR1) reinforcement schedule over 14 consecutive days. Behavioral validation via the open field test (OFT) demonstrated that propofol-exposed rats exhibited significantly enhanced spontaneous locomotor activity and attenuated anxiety-like states following training. RNA sequencing of prefrontal cortical tissue identified 174 differentially expressed genes (DEGs), with downregulated genes (n = 133) substantially predominating over upregulated ones (n = 41). Gene enrichment analysis revealed that upregulated DEGs were significantly enriched in pathways associated with oxidative stress injury, nitric oxide signaling, and hemoglobin-related oxygen metabolism, while downregulated DEGs were enriched in neuropeptide signaling pathways, responsive to psychostimulants and neurodegenerative disease, collectively suggesting a broad-scale inhibitory transcriptional remodeling of the prefrontal cortex under chronic propofol exposure. Glu-CEST MRI at 7.0T revealed a significant whole-brain elevation of glutamate levels in propofol-exposed rats relative to saline controls, with a particularly pronounced region-specific increase in the motor cortex, indicating there exists a disorder characterized by abnormal glutamate regulation within the central nervous system. These findings provide a multidimensional molecular and neuroimaging characterization of chronic propofol administration, identifying prefrontal cortical oxidative stress, neuropeptide system suppression, and dysregulated glutamate signaling as candidate pathological substrates, and highlighting Glu-CEST imaging as a promising non-invasive biomarker for anesthetic abuse.