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（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，我们和其他人研究了神经紧张素（NT）如何影响DA基底神经节和边缘通路的功能，以及它如何促进甲基苯丙胺的作用。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）反馈通路相关，在边缘结构中有类似的反馈安排，但不太清楚。对这些NT系统的全面刺激可减少DA介导的行为并抵消过度活跃的DA通路。因此，这些NT通路被归类为天然的神经镇静系统，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不仅能减轻DA反应，而且其通路受DA通过刺激D2和D1受体而相互调节，分别在基底节区和脑边缘区引起NT组织水平的相反降低和增加。与本提案相关的发现是，对非偶然低剂量和高剂量甲基苯丙胺的类似NT反应主要分别由相同的D2和D1受体介导。为了确定这些发现的临床相关性，我们使用了冰毒自我给药（SA）模型，该模型基于偶然杠杆压来获得冰毒输注，并观察到：(i) NT激动剂PD149163阻断冰毒SA，同时不替代冰毒，也不自我给药；（ii） PD149163在维持（即与稳定的冰毒SA相关的操作性反应）、消失开始（即不再与冰毒输注相关时消除杠杆按压）和恢复（大鼠在消失后对冰毒触发的杠杆按压反应）期间阻止杠杆按压；（iii）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，我们将检查行为和基底节区以及边缘NT/DA反应，以验证内源性NT系统在甲基苯丙胺SA的消失、维持和恢复中具有不同作用的假设，通过实现以下目标：具体目标A：确定NT系统和相关D2受体在甲基苯丙胺寻求行为（即减少杠杆压力）的消失中的作用。特异性目的B：确定NT系统和相关D1受体在甲基安非他明SA维持中的作用。特定目的C：确定甲基安非他明SA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.