Daiwile Atul P, Ladenheim Bruce, Jayanthi Subramaniam, Cadet Jean Lud
Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
Int J Mol Sci. 2025 Mar 18;26(6):2734. doi: 10.3390/ijms26062734.
Methamphetamine (METH) use disorder (MUD) is a public health catastrophe. Herein, we used a METH self-administration model to assess behavioral responses to the dopamine receptor D1 (DRD1) antagonist, SCH23390. Differential gene expression was measured in the dorsal striatum after a 30-day withdrawal from METH. SCH23390 administration reduced METH taking in all animals. Shock Resistant (SR) rats showed greater incubation of METH seeking, which was correlated with increased , , and mRNA expression. Cytoplasmic polyadenylation element binding protein 4 () mRNA levels were increased in shock-sensitive (SS) rats. SS rats also showed increased protein levels for cleavage and polyadenylation specificity factor (CPSF) and germ line development 2 (GLD2) that are CPEB4-interacting proteins. Interestingly, GLD2-regulated GLUN2A mRNA and its protein showed increased expression in the shock-sensitive rats. Taken together, these observations identified CPEB4-regulated molecular mechanisms acting via NMDA GLUN2A receptors as potential targets for the treatment of METH use disorder.
甲基苯丙胺（METH）使用障碍（MUD）是一场公共卫生灾难。在此，我们使用甲基苯丙胺自我给药模型来评估对多巴胺受体D1（DRD1）拮抗剂SCH23390的行为反应。在从甲基苯丙胺戒断30天后，测量背侧纹状体中的差异基因表达。给予SCH23390可减少所有动物的甲基苯丙胺摄入。抗休克（SR）大鼠表现出更强的甲基苯丙胺觅药潜伏期延长，这与 、 和 mRNA表达增加相关。休克敏感（SS）大鼠的细胞质多聚腺苷酸化元件结合蛋白4（ ）mRNA水平升高。SS大鼠还显示出与CPEB4相互作用的蛋白——切割和多聚腺苷酸化特异性因子（CPSF）和种系发育2（GLD2）的蛋白水平增加。有趣的是，GLD2调节的GLUN2A mRNA及其蛋白在休克敏感大鼠中表达增加。综上所述，这些观察结果确定了通过NMDA GLUN2A受体起作用的CPEB4调节的分子机制是治疗甲基苯丙胺使用障碍的潜在靶点。
