首页> 美国卫生研究院文献>The Journal of Pharmacology and Experimental Therapeutics >Extended Methamphetamine Self-Administration in Rats Results in a Selective Reduction of Dopamine Transporter Levels in the Prefrontal Cortex and Dorsal Striatum Not Accompanied by Marked Monoaminergic Depletion
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Extended Methamphetamine Self-Administration in Rats Results in a Selective Reduction of Dopamine Transporter Levels in the Prefrontal Cortex and Dorsal Striatum Not Accompanied by Marked Monoaminergic Depletion

机译:在大鼠中延长的甲基苯丙胺自我管理导致前额叶皮层和背侧纹状体中多巴胺转运蛋白水平的选择性降低但未伴有明显的单胺能消耗

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摘要

Chronic abuse of methamphetamine leads to cognitive dysfunction and high rates of relapse, paralleled by significant changes of brain dopamine and serotonin neurotransmission. Previously, we found that rats with extended access to methamphetamine self-administration displayed enhanced methamphetamine-primed reinstatement of drug-seeking and cognitive deficits relative to limited access animals. The present study investigated whether extended access to methamphetamine self-administration produced abnormalities in dopamine and serotonin systems in rat forebrain. Rats self-administered methamphetamine (0.02-mg/i.v. infusion) during daily 1-h sessions for 7 to 10 days, followed by either short- (1-h) or long-access (6-h) self-administration for 12 to 14 days. Lever responding was extinguished for 2 weeks before either reinstatement testing or rapid decapitation and tissue dissection. Tissue levels of monoamine transporters and markers of methamphetamine-induced toxicity were analyzed in several forebrain areas. Long-access methamphetamine self-administration resulted in escalation of daily drug intake (∼7 mg/kg/day) and enhanced drug-primed reinstatement compared with the short-access group. Furthermore, long-, but not short-access to self-administered methamphetamine resulted in persistent decreases in dopamine transporter (DAT) protein levels in the prefrontal cortex and dorsal striatum. In contrast, only minor alterations in the tissue levels of dopamine or its metabolites were found, and no changes in markers specific for dopamine terminals or glial cell activation were detected. Our findings suggest that persistent methamphetamine seeking is associated with region-selective changes in DAT levels without accompanying monoaminergic neurotoxicity. Greater understanding of the neuroadaptations underlying persistent methamphetamine seeking and cognitive deficits could yield targets suitable for future therapeutic interventions.
机译:甲基苯丙胺的长期滥用会导致认知功能障碍和高复发率,同时脑多巴胺和5-羟色胺神经递质的显着变化会导致这种情况。以前,我们发现与甲基苯丙胺自我给药相比,具有扩展通路的大鼠相对于有限通路的动物而言,具有增强的甲基苯丙胺引发的药物寻找和认知缺陷恢复能力。本研究调查了甲基苯丙胺自我给药的延长使用是否在大鼠前脑多巴胺和5-羟色胺系统中产生异常。大鼠在每天1小时的疗程中自行服用甲基苯丙胺(0.02 mg / iv输注),持续7至10天,然后以短时间(1-h)或长时间服用(6h)自体服用12至14天在恢复测试或快速断头并组织解剖之前,将反应杆熄灭2周。在几个前脑区域分析了单胺转运蛋白的组织水平和甲基苯丙胺诱导的毒性标志物。与短疗程组相比,长期服用甲基苯丙胺导致每日药物摄入量增加(约7 mg / kg /天),药物引发的恢复也有所提高。此外,长期但并非短期接触自我管理的甲基苯丙胺会导致额叶前额叶皮层和背侧纹状体中多巴胺转运蛋白(DAT)蛋白水平持续下降。相反,仅发现了多巴胺或其代谢物的组织水平的微小变化,并且未检测到对多巴胺末端或神经胶质细胞活化具有特异性的标志物的变化。我们的发现表明,持续的甲基苯丙胺搜寻与DAT水平的区域选择性变化相关,而没有伴随的单胺能神经毒性。对持续存在的甲基苯丙胺寻求和认知缺陷的神经适应的更多了解可能会产生适合将来治疗干预的靶点。

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