Hatzipetros Theo, Raudensky Jamie G, Soghomonian Jean-Jacques, Yamamoto Bryan K
Laboratory of Neurochemistry, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
J Neurosci. 2007 May 30;27(22):5895-902. doi: 10.1523/JNEUROSCI.5260-06.2007.
The therapeutic management of methamphetamine (METH)-induced psychoses often involves treatment with the typical antipsychotic drug and dopamine D2 receptor antagonist haloperidol. We report here that subchronic haloperidol administration after a high-dose regimen of METH produces a heretofore unrecognized toxicity to GABAergic cells, as reflected by GAD67 mRNA expression histochemistry, in the rat substantia nigra pars reticulata (SNr) through an acute and persistent augmentation of glutamate release, NMDA receptor activation, and DNA fragmentation. The dopaminergic cells in the substantia nigra pars compacta were unaffected by METH or haloperidol alone or the combination of METH and haloperidol. These findings suggest that the current therapeutic management of METH-induced psychoses with haloperidol may be contraindicated because of a resultant GABAergic cell death in the SNr, which may predispose some individuals to the development of hyperkinetic movement disorders and seizures.
甲基苯丙胺（METH）所致精神病的治疗管理通常涉及使用典型抗精神病药物及多巴胺D2受体拮抗剂氟哌啶醇进行治疗。我们在此报告，在高剂量METH给药方案后亚慢性给予氟哌啶醇，会对大鼠黑质网状部（SNr）的GABA能细胞产生一种迄今未被认识到的毒性，这通过谷氨酸脱羧酶67（GAD67）mRNA表达组织化学得以体现，其机制是谷氨酸释放急性且持续增加、NMDA受体激活以及DNA片段化。黑质致密部的多巴胺能细胞单独受METH或氟哌啶醇影响，以及受METH与氟哌啶醇联合影响时均未受影响。这些发现表明，目前用氟哌啶醇治疗METH所致精神病的治疗管理可能是禁忌的，因为这会导致SNr中的GABA能细胞死亡，这可能使一些个体易患运动亢进性运动障碍和癫痫发作。
