Neurotoxicity in the adult rat following chronic exposure to methamphetamine

预处理甲基苯丙胺（冰毒）可以减轻毒性由于急性冰毒挑战。大多数先前的报告主要集中在药物对纹状体多巴胺能系统的影响上。在目前的研究中，我们采用了一种方案，包括逐渐增加对大鼠的甲基苯丙胺给药，以模仿一些人类甲基苯丙胺成瘾者使用的逐渐增加的药物剂量。我们发现，这种甲基安非他明预处理与纹状体和皮层中由甲基安非他明刺激（5 mg/kg x 6次注射，间隔1小时）引起的多巴胺消耗的完全保护有关。相比之下，在纹状体和海马体中没有预先调节介导的保护作用，但在皮层中观察到一些保护作用。在海马体中，对甲基苯丙胺诱导的去甲肾上腺素（NE）耗竭也没有保护作用。这些结果表明，与目前的教条相反，冰毒对啮齿动物大脑单胺能系统的毒性作用可能存在不同的机制。因此，长期注射冰毒可能会激活防止多巴胺毒性的程序，而不会影响药物引起的血清素能系统的病理变化。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. 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.