Role of Neurotensin Systems in Methamphetamine Self Administration

描述（由申请人提供）：甲基苯丙胺（METH）改变单胺能（例如多巴胺能; DA）系统，导致难治性依赖和精神病、暴力和犯罪行为。由于没有FDA批准的药物可用于治疗METH依赖，国家药物滥用研究所（NIDA）鼓励研究导致METH依赖的CNS系统，以确定新的治疗策略。因此，其他人和我们研究神经降压素（NT）如何影响DA基底神经节和边缘系统通路的功能，以及它如何有助于METH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）反馈途径相关，在边缘结构中具有相似但不太清楚的反馈安排。这些NT系统的整体刺激减少DA介导的行为和抵消过度活跃的DA途径。因此，这些NT途径已被归类为天然的神经安定剂系统和NT激动剂已建议由NIDA作为可能的药物治疗药物滥用。据报道，NT不仅减轻DA反应，而且其途径受到DA的间接调节，刺激D2和D1受体分别引起基底神经节和边缘脑区域中NT组织水平的相反降低和增加。与本建议相关的发现是，对非偶然的低剂量和高剂量的METH的类似NT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，我们使用基于偶然杠杆按压的METH自我给药（SA）模型以获得METH输注，并观察到：（i）NT激动剂PD 149163阻断METH SA，而不是METH的替代物，也不是自我给药本身;（ii）PD 149163阻断维持期间的杠杆按压（即，与稳定METHSA相关的操作性反应），消退的开始（即，当不再与METH输注相关时消除杠杆按压）和恢复（大鼠对消退后给予的METH触发的杠杆按压反应）;（iii）与D2和D1机制相关的内源性NT系统分别对与消退和维持相关的行为有不同的贡献。基于这些发现，我们将检查行为和基底神经节和边缘NT/DA反应，以通过实现以下目标来检验内源性NT系统在METH SA的消退、维持和恢复中具有不同作用的假设：具体目标A：确定NT系统和相关D2受体对METH寻求行为消退的作用（即，减少杠杆按压）。具体目的B：确定NT系统和相关D1受体对METH SA维持的作用。具体目标C：确定METH SA恢复对NT系统的影响。 公共卫生相关性：甲基苯丙胺（METH）滥用造成严重的个人和社会伤害。我们的大量研究表明，基底神经节和边缘神经降压素（NT）系统对多巴胺（DA）D1和D2调节敏感，并进而通过抑制性反馈机制帮助影响大鼠对非偶然METH治疗的反应。为了确定这些发现与METH滥用的临床相关性，我们正在研究METH自我给药（取决于杠杆按压）对与背侧纹状体和背侧核相关的NT通路的影响。我们已经确定，NT系统响应于在我们的自我管理METH模型的维护，灭绝，和恢复的对比方式，内源性NT系统特别有助于消除杠杆按压灭绝期间，以及缺乏杠杆按压在少数“无响应”大鼠在维护期间。由于这些发现，我们建议测试的具体假设，即内源性NT系统有不同的作用，灭绝，维护和恢复METH自我管理。

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. PUBLIC HEALTH RELEVANCE: Methamphetamine (METH) abuse inflicts severe personal and societal harm. Our extensive studies have suggested that basal ganglia and limbic neurotensin (NT) systems are sensitive to dopamine (DA) D1 and D2 regulation and in turn through inhibitory feedback mechanism help to influence the response in rats to non- contingent METH treatment. To determine the clinical relevance of these findings to METH abuse, we are studying the impact of METH self-administration (contingent on lever pressing) on the NT pathways associated with the dorsal striatum and nucleus accumbens. We have determined that NT systems respond in contrasting ways to maintenance, extinction, and reinstatement in our self-administration METH model and that endogenous NT systems specifically contribute to the elimination of lever pressing during extinction as well as a lack of lever pressing in a minoriy of "non-responding" rats during maintenance. Because of these findings we propose to test the specific hypothesis that endogenous NT systems have differential roles in the extinction, maintenance, and reinstatement of METH self-administration.