Dopamine Partial Agonists and Psychostimulant Dependence

描述（由申请人提供）：甲基苯丙胺仍然是一种主要的滥用药物，与显著的行为和身体毒性有关。上一个资助期的工作表明，多巴胺部分激动剂阻断甲基苯丙胺的强化作用，并阻断与甲基苯丙胺戒断相关的奖励不足。其他研究的特征是甲基苯丙胺自我给药随着使用时间的延长而逐渐增加（递增），在初步研究中，多巴胺部分激动剂治疗阻断了甲基苯丙胺在递增模型中的强化作用。本系列研究的目的是利用扩展访问（升级）模型来探索多巴胺部分激动剂和完全直接激动剂对成瘾周期的各个阶段的影响。大鼠将被植入静脉颈静脉导管，并接受训练以自行静脉注射甲基苯丙胺。将在具体目标1中探索促进使用扩展后摄入量增加的因素（剂量、治疗时间、治疗间期和停药）的进一步表征。部分多巴胺激动剂对甲基苯丙胺长期使用期间观察到的自我给药增加（递增）的影响将在具体目标2中探索。多巴胺部分激动剂对与从长期接触甲基苯丙胺中戒断相关的奖赏缺陷的影响将在具体目标3中探讨。将在具体目标4中探索长期获得甲基苯丙胺自我给药对神经毒性诱导多巴胺水平、GFAP和DAT免疫细胞化学测量值和细胞凋亡的影响以及多巴胺部分激动剂的影响。拟议研究的结果不仅将提供新的见解甲基苯丙胺自我管理的神经药理学机制，但也将提供新的动物模型和神经药理学数据，以评估甲基苯丙胺滥用和依赖的潜在药物。

DESCRIPTION (provided by applicant): Methamphetamine continues to be a major drug of abuse associated with significant behavioral and physical toxicity. Work during the previous funding period has shown that dopamine partial agonists block the reinforcing actions of methamphetamine and block the reward deficits associated with methamphetamine withdrawal. Additional studies have characterized a progressive increase in methamphetamine selfadministration with extended access (escalation), and in preliminary studies treatment with dopamine partial agonists block the reinforcing effects of methamphetamine in the escalation model. The purpose of the present series of studies is to exploit the extended access (escalation) model to explore the effects of dopamine partial agonists and full direct agonists on various stages of the addiction cycle. Rats will be implanted with intravenous jugular catheters and trained to self-administer methamphetamine intravenously. Further characterization of the factors that promote escalation in intake with extended access (dose, time of session, intersession intervals and withdrawal) will be explored in Specific Aim 1. The effects of partial dopamine agonists on the increased self-administration observed during extended access to methamphetamine (escalation) will be explored in Specific Aim 2. The effects of dopamine partial agonists on reward deficits associated with withdrawal from extended access to methamphetamine will be explored in Specific Aim 3. The effects of prolonged access to methamphetamine self-administration on measure or neurotoxicity inducing dopamine levels, GFAP and immunocytochemistry measures of DAT and apoptosis and the effects of dopamine partial agonists will be explored in Specific Aim 4. The results of the proposed studies will not only provide novel insights into the neuropharmacological mechanisms of methamphetamine self-administration, but also will provide novel animal models and neuropharmacological data with which to assess potential medications for methamphetamine abuse and dependence.