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。前一个资助期的工作表明，多巴胺部分激动剂可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赏缺失。更多的研究表明，甲基苯丙胺的自我给药逐渐增加，并扩大了接触(升级)，在初步研究中，用多巴胺部分激动剂治疗阻止了甲基苯丙胺在升级模型中的强化作用。本系列研究的目的是利用扩展通路(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不同阶段的影响。大鼠将被植入静脉颈静脉导管，并接受静脉注射甲基苯丙胺的训练。将在特定目标1中探索促进延长获得甲基苯丙胺的摄入量增加的因素(剂量、服药时间、间歇时间和戒断)的进一步特征。部分多巴胺激动剂对延长获得甲基苯丙胺(逐步增加)期间观察到的自我给药增加的影响将在特定目标2中探讨。多巴胺部分激动剂对与停止延长获得甲基苯丙胺有关的奖赏缺陷的影响将在特定目标3中探索。长期获得甲基苯丙胺自我给药对测量或神经毒性诱导的多巴胺水平的影响，GFAP、DAT和细胞凋亡的免疫细胞化学方法以及多巴胺部分激动剂的作用将在特定的目标4中进行探索。建议的研究结果不仅将为甲基苯丙胺自我给药的神经药理学机制提供新的见解，而且将为评估甲基苯丙胺滥用和依赖的潜在药物提供新的动物模型和神经药理学数据。

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.