メトカチノンによるラット前頭前野の神経毒性：統合されたシナプス変化とトランスクリプトーム解析

Long-term abuse of methcathinone reduces grey matter volume in the prefrontal cortex and consequently impairs learning and memory abilities. However, the exact mechanism of damage remains unknown. Therefore, this study aimed to analyse the potential mechanisms underlying methcathinone-induced neural damage using transcriptomic analysis. Accordingly, 32 Sprague Dawley rats were randomly divided into four groups: control, low-dose, medium-dose and high-dose. Low, medium and high methcathinone doses (0.25, 5 and 20 mg/kg) were administered to the animals in the three treatment groups once daily via intraperitoneal injection for 2 weeks. Finally, the learning and memory functions of all the animals were tested using the Morris water maze. Electron microscopy and Golgi staining were used to observe changes in synaptic structure, and transcriptome sequencing was performed in the prefrontal cortex of the control and high-dose groups. Key differentially expressed genes were quantified using quantitative real-time reverse transcription polymerase chain reaction. Collectively, methcathinone induced learning and memory decline in rats and destroyed the synaptic structure of the rat prefrontal cortex. In the transcriptomic analysis, 1457 (694 up-regulated and 763 down-regulated) genes were differentially expressed in the prefrontal cortex of rats in the high-concentration group compared to that in the control group. Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes analysis revealed that differential genes were enriched in synapses, neurotransmitter systems, homeostasis of Ca²⁺ concentration and membrane potential regulation. This indicates that methcathinone adversely affects neurotransmitter regulation, Ca²⁺ signalling and membrane potential regulation, thereby destroying synapse structure and causing learning and memory dysfunction. Combined with the above molecular mechanisms, seven key genes were identified: nerve growth factor (NGF), dopamine receptor D1 (DRD1), dopamine receptor D2 (DRD2), solute carrier family 1 member 2 (SLC1A2), calcium/calmodulin-dependent protein kinase II alpha (CAMK2A), synaptotagmin 1 (SYT1) and glutamate ionotropic receptor N-methyl-d-aspartate type subunit 2A (GRIN2A). This study demonstrates that methcathinone causes neural damage and provides possible molecular mechanisms and target genes to clarify the mechanism of methcathinone-induced neural damage.