Neuroimaging Correlates of Cocaine Reinforcement for Cognitive Performance

描述（由申请人提供）：本研究项目的目的是评估非人灵长类动物（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成功表现的奖励。有证据表明，在NHP的大脑结构的影响，可卡因作为奖励的会议内的食欲（果汁）奖励也可用的信号试验的介绍。该项目将利用由多对象延迟匹配样本（DMS）任务组成的特征明确的短期记忆/执行功能范例。该任务提供了用于测试在任何给定试验上的“认知负荷”是否与与前额叶皮层（PFC）、内侧颞叶（MTL）和背侧和腹侧纹状体（Str）中的功能性神经元活动相关的表现直接相关，所述功能性神经元活动从相同的行为会话成像。拟议的研究将确定在这种模式下，认知处理如何受到急性和长期暴露于可卡因的影响，以及目前在人类临床研究中使用的药物如何改变可卡因对认知功能的有害影响。目的1和2将评估和表征上述三个脑区的18FDG脑代谢活动的PET成像，并确定可卡因奖励对DMS任务表现的影响。目标3将研究可卡因奖励认知表现的影响，作为动物选择可卡因与果汁信号试验的偏好的函数。这些分析将根据可卡因与果汁试验的选择在个体动物中部分排除可卡因效应，并检查上述三个脑区域中18FDG脑代谢活动的PET成像差异，以确定在相同DMS范例中偏好可卡因与果汁奖励试验的动物的功能差异。目标3还将上述分析扩展到在为期六个月的日常测试期间以相同随机方式重复暴露于可卡因和食欲奖励的条件的动物。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，以确定作为目标4的一部分施用的药剂的长期有效性。目的4将研究上述行为和18 FDG成像如何与DMS任务中的认知需求变化相关，作为两种候选治疗药物（莫达非尼和下丘脑泌素-1受体拮抗剂SB 334867）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模式中的强化作用，目前被认为是在人类临床试验中治疗可卡因成瘾的可能化合物。这些药物在测试的早期阶段的这些作用将与长期暴露于相同范例后的作用进行比较，使用表现和偏好测量作为可卡因作用变化的指标，与改变的18FDG成像相关。

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.