Effect of Methamphetamine Self-Administration on Neurotensin Systems of the Basal Ganglia
Effect of Methamphetamine Self-Administration on Neurotensin Systems of the Basal Ganglia
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DOI：
10.1124/jpet.110.176610
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发表时间：
2011-03-01
影响因子：
3.5
通讯作者：
Hanson, Glen R.
中科院分区：
文献类型：
--
作者：
Frankel, Paul S.;Hoonakker, Amanda J.;Hanson, Glen R.
甲基苯丙胺（METH）依赖会造成令人震惊的个人和社会损害。尽管与滥用METH相关的许多问题都与其对多巴胺（DA）基底神经节系统的深刻作用有关，但目前还没有批准的药物来治疗METH成瘾。基于这个原因，我们和其他人研究了METH诱导的基底神经节神经降压素（NT）系统的反应。这种神经肽与黑质纹状体DA投射的抑制性反馈途径相关，并且NT组织水平在对高剂量的非偶然性METH的反应中升高，因为其在纹状体黑质途径中的合成增加。本研究报告的应急反应NT在基底神经节自我管理的甲基（SAM）。静脉注射METH与大鼠适当的按压行为相关，显著升高背侧纹状体（210%）和黑质（202%）的NT含量。在这些相同的结构中，NT水平也升高，在轭METH动物（160和146%，分别），但不一样多的SAM大鼠。这些作用被D1拮抗剂阻断，但不被D2拮抗剂阻断。NT激动剂前5天的操作性行为阻断应激反应大鼠的行为，但NT拮抗剂对这种行为没有显着影响。这是首次报道与纹状体黑质通路相关的NT系统在METH自我给药期间发生显著改变，我们的研究结果表明，在维持操作性反应期间NT受体的激活减少了相关的神经元压迫行为。
Methamphetamine (METH) dependence causes alarming personal and social damage. Even though many of the problems associated with abuse of METH are related to its profound actions on dopamine (DA) basal ganglia systems, there currently are no approved medications to treat METH addiction. For this reason, we and others have examined the METH-induced responses of neurotensin (NT) systems in the basal ganglia. This neuropeptide is associated with inhibitory feedback pathways to nigrostriatal DA projections, and NT tissue levels are elevated in response to high doses of noncontingent METH because of its increased synthesis in the striatonigral pathway. The present study reports the contingent responses of NT in the basal ganglia to self-administration of METH (SAM). Intravenous infusions of METH linked to appropriate lever-pressing behavior by rats significantly elevated NT content in both dorsal striatum (210%) and substantia nigra (202%). In these same structures, NT levels were also elevated in yoked METH animals (160 and 146%, respectively) but not as much as in the SAM rats. These effects were blocked by a D1, but not D2, antagonist. A NT agonist administered before the day 5 of operant behavior blocked lever-pressing behavior in responding rats, but a NT antagonist had no significant effect on this behavior. These are the first reports that NT systems associated with striatonigral pathway are significantly altered during METH self-administration, and our findings suggest that activation of NT receptors during maintenance of operant responding reduces the associated lever-pressing behavior.