Alterations of Glucose Uptake and Protein Expression Related to the Insulin Signaling Pathway in the Brain of Phenobarbital-Addictive Rats by 18F-FDG PET/CT and Proteomic Analysis.

Drug addiction is a chronic relapsing brain disease. Alterations of glucose uptake and metabolism are found in the brain of drug addicts. Insulin mediates brain glucose metabolism and its abnormality could induce brain injury and cognitive impairment. Here, we established a rat model of phenobarbital addiction by 90 days of dose escalation and evaluated addiction-related symptoms. We also performed 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) to detect glucose uptake in the brain and proteomic analysis of the function of the differentially expressed (DE) proteins via bioinformatics in brain tissues by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) on days 60 and 90 of phenobarbital or 0.5% carboxymethyl cellulose sodium (CMC-Na) (vehicle) administration. The results showed that phenobarbital-addictive rats developed severe withdrawal symptoms after abstinence and glucose uptake was significantly increased in the brain. Proteomics analysis showed that numerous DE proteins were enriched after phenobarbital administration, among which CALM1, ARAF, and Cbl proteins (related to the insulin signaling pathway) were significantly downregulated on day 60 but not day 90. However, SLC27A3 and NF-κB1 proteins (related to insulin resistance) were significantly upregulated on day 90 (data are available via ProteomeXchange with identifier PXD021101). Our data indicate that the insulin signaling pathway and insulin resistance may play a role in the development of phenobarbital addiction and brain injury, so the findings may have important clinical implications.