Neuroimaging Correlates of Cocaine Reinforcement for Cognitive Performance

描述(申请人提供)：本研究项目的目的是评估非人类灵长类动物(NHP)在认知任务中信息处理过程中大脑的变化，该任务涉及暴露于可卡因作为对成功表现的奖励。有证据表明，在有食欲(果汁)奖励的情况下，在有信号的试验中引入可卡因作为奖励，会影响NHP的大脑结构。该项目将利用一个特征良好的短期记忆/执行功能范例，包括一个多对象延迟匹配到样本(DMS)任务。这项任务旨在测试在任何给定试验中，“认知负荷”是否与表现直接相关，这些表现与同一行为过程中拍摄到的前额叶(PFC)、内侧颞叶(MTL)以及背侧和腹侧纹状体(STR)的功能性神经元活动有关。拟议的研究将确定在这一范式中，急性和长期接触可卡因如何影响认知过程，以及目前用于人类临床研究的制剂如何改变可卡因对认知功能的有害影响。AIMS 1和2将评估和表征上述三个脑区的18FDG大脑代谢活动的PET成像，并确定可卡因奖励对DMS任务绩效的影响。目标3将考察可卡因对认知能力的影响，作为动物选择可卡因还是果汁信号试验的函数。这些分析将根据可卡因和果汁试验的选择，部分找出可卡因对单个动物的影响，并检查上述三个大脑区域18FDG大脑代谢活动的PET成像差异，以确定在相同的DMS范例中，倾向于可卡因和果汁奖励试验的动物的功能差异。AIM 3还将把上述分析扩展到在六个月的日常测试中以相同的随机方式实施可卡因和食欲奖励的反复暴露的动物。在这段时间内，DMS反应(表现)和对可卡因与果汁奖励的偏好以及相关神经元相关性的变化将被确定为基线，以确定作为Aim 4一部分的药物的长期有效性。Aim 4将研究上述行为和18FDG成像如何与DMS任务中认知需求的变化相关，作为两种候选治疗药物-莫达非尼和下丘脑肌醇-1受体拮抗剂SB334867的先前治疗的函数，这两种药物可以改变可卡因在自我给药范例中的增强效果，目前被认为是治疗可卡因成瘾的人类临床试验中可能的化合物。在测试的早期阶段，这些药物的这些作用将与长期接触相同范例后的效果进行比较，方法是使用性能和偏好测量作为可卡因作用变化的指示器，并与18FDG成像改变相关。

DESCRIPTION (provided by applicant): The purpose of this research project is to assess changes in the brains of nonhuman primates (NHPs) during information processing in a cognitive task that involves exposure to cocaine as a reward for successful performance. Evidence is presented that structures in the brain of NHPs are affected by the introduction of cocaine as a reward on signaled trials within a session where appetitive (juice) rewards are also available. The Project will utilize a well-characterized short-term memory/executive function paradigm consisting of a multi- object delayed match to sample (DMS) task. The task provides for testing whether the "cognitive load" on any given trial is directly related to performance in association with the functional neuronal activity in prefrontal cortex (PFC), medial temporal lobe (MTL) and dorsal and ventral striatum (Str) that is imaged from the same behavioral sessions. The proposed studies will determine how cognitive processing is affected by acute and long-term exposure to cocaine in this paradigm and how agents currently utilized in human clinical studies alter the detrimental effects of cocaine on cognitive function. Aims 1 and 2 will assess and characterize PET imaging of 18FDG brain metabolic activity in the above three brain regions and determine the effects of cocaine rewards on performance of the DMS task. Aim 3 will examine the effects of cocaine rewarded cognitive performance as a function of the animal's preference for choosing cocaine vs. juice signaled trials. These analyses will partial out cocaine effects across individual animals in terms of their choice of cocaine vs. juice trials and examine difference in PET imaging of 18FDG brain metabolic activity in the above three brain regions to determine functional differences in animals that prefer cocaine vs. juice rewarded trials in the same DMS paradigm. Aim 3 will also extend the above analyses to animals that are repeatedly exposed to conditions in which cocaine and appetitive rewards are implemented in the same random manner during day-to-day testing for a period of six months. Changes in DMS responding (performance) and preferences for cocaine vs. juice rewards and associated neuronal correlates over this time period will be determined as a baseline for in order to ascertaining the long-term effectiveness of agents administered as part of Aim 4. Aim 4 will examine how the above behavioral and 18FDG imaging correlates of cognitive demand in the DMS task change as a function of prior treatment with two candidate treatment agents, Modafinil and the hypocretin-1 receptor antagonist SB334867, that can alter cocaine's reinforcing effects in self-administration paradigms and are currently considered as possible compounds to treat cocaine addiction in human clinical trials. These actions of these drugs in the early phase of testing will be compared with the effects following long-term exposure to the same paradigm using performance and preference measures as indicants of changes in cocaine's actions in association with altered 18FDG imaging correlates.