Neurotoxicity in the adult rat following chronic exposure to methamphetamine

用甲基苯丙胺(甲基苯丙胺)预处理可以减轻由于急性冰毒挑战而产生的毒性。以前的大多数报道主要集中在该药物对纹状体多巴胺能系统的影响。在目前的研究中，我们使用了一种方案，包括逐步增加对大鼠的冰毒注射，以便模仿一些人类冰毒成瘾者使用的逐渐大剂量的药物。我们发现，这种冰毒预适应能完全保护纹状体和大脑皮层免受冰毒攻击(5 mg/kg×6次注射，间隔1小时)引起的多巴胺耗竭。相反，纹状体和海马区的5-羟色胺耗竭没有预适应介导的保护作用，在皮质观察到了一些保护作用。对冰毒诱导的海马区去甲肾上腺素(NE)耗竭也没有保护作用。这些结果表明，与目前的学说相反，甲基毒性对啮齿类动物大脑单胺能系统的作用机制可能有所不同。因此，长期注射冰毒可能会激活保护多巴胺毒性的程序，而不会影响药物诱导的5-羟色胺能系统的病理变化。进一步的研究将需要评估这些差异反应的细胞和分子基础。

Pretreatment with methamphetamine (METH) can attenuate toxicity due to acute METH challenges. The majority of previous reports have focused mainly on the effects of the drug on the striatal dopaminergic system. In the present study, we used a regimen that involves gradual increases in METH administration to rats in order to mimic progressively larger doses of the drug used by some human METH addicts. We found that this METH preconditioning was associated with complete protection against dopamine depletion caused by a METH challenge (5 mg/kg x 6 injections given 1 h apart) in the striatum and cortex. In contrast, there was no preconditioning-mediated protection against METH-induced serotonin depletion in the striatum and hippocampus, with some protection being observed in the cortex. There was also no protection against METH-induced norepinephrine (NE) depletion in the hippocampus. These results indicate that, in contrast to the present dogmas, there might be differences in the mechanisms involved in METH toxicity on monoaminergic systems in the rodent brain. Thus, chronic injections of METH might activate programs that protect against dopamine toxicity without influencing drug-induced pathological changes in serotoninergic systems. Further studies will need to evaluate the cellular and molecular bases for these differential responses.