Effects of Chronic Ephedrine Toxicity on Functional Connections, Cell Apoptosis, and CREB-Related Proteins in the Prefrontal Cortex of Rhesus Monkeys.

Ephedrine abuse has spread in many parts of the world, severely threatening human health. The mechanism of ephedrine toxicity is still unclear. To explore the possible neural mechanisms of ephedrine toxicity, this study established a non-human primate model of ephedrine exposure, analyzed the functional connectivity changes in its prefrontal cortex through resting state BOLD-fMRI, and then inspected the pathophysiological changes as well as the expression of the cyclic adenosine monophosphate response element-binding protein (CREB), phosphorylated CREB (P-CREB), and CREB target proteins (c-fos and fosB) in the prefrontal cortex. After ephedrine toxicity, we found that the prefrontal cortex of monkeys strengthened its functional connectivity with the brain regions that perform motivation, drive, reward, and learning and memory functions and weakened its functional connectivity with the brain regions that perform cognitive control. These results suggest that ephedrine toxicity causes abnormal neural circuits that lead to the amplification and enhancement of drug-related cues and the weakening and damage of cognitive control function. Histology showed that the neurocytotoxicity of ephedrine can cause neuronal degeneration and apoptosis. Real-time PCR and Western blot showed increased expression of CREB mRNA and CREB/P-CREB/c-fos/fosB protein in the prefrontal cortex after ephedrine toxicity. Collectively, the present study indicates that the enhancement of drug-related cues and the weakening of cognitive control caused by abnormal neural circuits after drug exposure may be a major mechanism of brain function changes caused by ephedrine. These histological and molecular changes may be the pathophysiological basis of brain function changes caused by ephedrine.