Neurotoxicity in the adult rat following chronic exposure to methamphetamine

用甲基苯丙胺（METH）预处理可以减轻急性METH攻击引起的毒性。以前的大多数报告主要集中在药物对纹状体多巴胺能系统的影响。在本研究中，我们使用了一种方案，涉及逐渐增加对大鼠的METH给药，以模仿一些人类METH成瘾者使用的逐渐更大剂量的药物。我们发现，这种METH预处理与纹状体和皮质中由METH攻击（5 mg/kg x 6次注射，间隔1 h）引起的多巴胺耗竭的完全保护相关。相比之下，在纹状体和海马中没有预处理介导的对MET诱导的5-羟色胺耗竭的保护，在皮质中观察到一些保护。也没有保护对甲基诱导的去甲肾上腺素（NE）消耗海马。这些结果表明，与目前的教条相反，METH对啮齿动物脑中单胺能系统的毒性机制可能存在差异。因此，长期注射METH可能会激活保护多巴胺毒性的程序，而不会影响多巴胺能系统中药物诱导的病理变化。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。 此外，我们已经开始调查与长期使用甲基苯丙胺等药物有关的表观遗传变化。我们发现组蛋白去乙酰化在调节背侧纹状体谷氨酸受体中起重要作用。 大鼠正在接受METH SA，然后进行复发测试。我们已经确定了钾通道在METH SA戒断中的潜在作用。我们还表明，DA受体拮抗剂可以阻断METH SA。我们还发现了大麻素系统的变化。

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. In addition, we have begun to investigate the epigenetic changes that are associated with the chronic use of drugs such as methamphetamine. We have found evidence that histone de-acetylation plays an important role in regulating glutamate receptors in the dorsal striatum. Rats are undergoing METH SA followed by tests of relapse. We have identified the potential role of potassium channels in abstinence from METH SA. We have also shown that DA receptor antagonism can block METH SA. We have also identified changes in the cannabinoid systems.