Role of Neurotensin Systems in Methamphetamine Self Administration

描述(由申请人提供)：甲基苯丙胺(冰毒)改变单胺系统(例如，多巴胺能；DA)，导致顽固的依赖和精神、暴力和犯罪行为。由于没有FDA批准的药物可用于治疗冰毒依赖，美国国家药物滥用研究所(NIDA)鼓励对导致冰毒依赖的中枢神经系统进行研究，以确定新的治疗策略。因此，其他人和我们研究了神经降压素(NT)如何影响DA基底节和边缘通路的功能，以及它如何参与冰毒的作用。NT是一种神经肽，与黑质纹状体DA投射的间接(D2调节)和直接(D1调节)反馈通路有关，在边缘结构中也有类似但较不清楚的反馈排列。总体而言，这些NT系统的刺激减少了DA介导的行为，并抵消了过度活跃的DA通路。因此，这些NT途径被归类为天然的抗神经药系统，NIDA建议将NT激动剂作为治疗药物滥用的可能药物。据报道，NT不仅减轻DA反应，而且其通路受DA的相互调节，刺激D2和D1受体分别导致基底节和边缘脑区NT组织水平的相反降低和升高。与本建议相关的发现是，类似的NT对非偶然低剂量和高剂量冰毒的反应主要分别由这些相同的D2和D1受体介导。为了确定这些发现的临床相关性，我们使用了基于或有杠杆按压的冰毒自我给药(SA)模型来获得冰毒输注，并观察到：(I)NT激动剂PD149163在不替代冰毒的情况下阻断冰毒SA，但本身也不是自我给药；(Ii)PD149163在维持(即与稳定的冰毒SA相关的操作性反应)、灭绝开始(即不再与冰毒注射挂钩时消除杠杆按压)和恢复(大鼠在灭绝后对冰毒触发的杠杆按压反应)期间阻断杠杆按压；(3)与D2和D1机制相关的内源性NT系统分别对与灭绝和维持相关的行为有不同的贡献。基于这些发现，我们将研究行为、基底节和边缘的NT/DA反应，以检验内源性NT系统在冰毒SA的消退、维持和恢复中具有不同作用的假设，具体目的如下：A：确定NT系统和相关的D2受体在消退寻求冰毒行为(即减少杠杆按压)中的作用。特定目的B：确定NT系统和相关的D1R在甲基苯丙氨酸维持中的作用。具体目标C：确定冰毒恢复对NT系统的影响。

DESCRIPTION (provided by applicant): Methamphetamine (METH) alters monoaminergic (e.g. dopaminergic; DA) systems leading to a refractory dependence and psychotic, violent and criminal behaviors. Because no FDA-approved medications are available to treat METH dependence, the National Institute on Drug Abuse (NIDA) has encouraged research of CNS systems that contribute to METH dependence to identify novel therapeutic strategies. Thus, others and we study how neurotensin (NT) influences the function of DA basal ganglia and limbic pathways and how it contributes to the effects of METH. NT is a neuropeptide associated with both the indirect (D2-regulated) and direct (D1-regulated) feedback pathways to the nigrostriatal DA projection, with similar, but less well delineated, feedback arrangements in limbic structures. Overall stimulation of these NT systems reduces DA-mediated behaviors and counteracts overactive DA pathways. Consequently, these NT pathways have been classified as natural neuroleptic systems and NT agonists have been suggested by NIDA as possible medications for treating drug abuse. It has been reported that not only does NT mitigate DA responses, but its pathways are reciprocally regulated by DA with stimulation of D2 and D1 receptors causing opposing decreases and increases of NT tissue levels, respectively, in both basal ganglia and limbic brain regions. Relevant to the present proposal are findings that similar NT responses to non-contingent low and high doses of METH are principally mediated by these same D2 and D1 receptors, respectively. In order to determine the clinical relevance of these findings, we used METH self-administration (SA) models based on contingent lever pressing to obtain METH infusion and observed that: (i) the NT agonist, PD149163 blocks METH SA while not substituting for METH nor being self-administered per se; (ii) PD149163 blocks lever pressing during maintenance (i.e., operant responses associated with stable METH SA), beginning of extinction (i.e., elimination of lever pressing when no longer linked to METH infusion) and reinstatement (the lever- pressing response of rats to a METH trigger given after extinction); (iii) endogenous NT systems linked to D2 and D1 mechanisms, differentially contribute to behaviors associated with extinction and maintenance, respectively. Based on these findings, we will examine behavioral and basal ganglia and limbic NT/DA responses to test the hypothesis that endogenous NT systems have differential roles in extinction, maintenance and reinstatement of METH SA, by achieving the following: Specific Aim A: Determine the role of NT systems and related D2 receptors on extinction of METH- seeking behavior (i.e., reduced lever pressing). Specific Aim B:Determine the role of NT systems and related D1 receptors on METH SA maintenance. Specific Aim C: Determine the effect of METH SA reinstatement on NT systems.