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类灵长类动物（NHPs）在认知任务中信息处理过程中的大脑变化，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，在有食欲（果汁）奖励的情况下，在信号试验中引入可卡因作为奖励会影响NHPs的大脑结构。该项目将利用具有良好特征的短期记忆/执行功能范例，包括多对象延迟匹配样本（DMS）任务。该任务提供测试任何给定试验中的“认知负荷”是否与在相同行为会话中成像的前额叶皮层（PFC）、内侧颞叶（MTL）和背腹纹状体（Str）的功能性神经元活动的表现直接相关。拟议的研究将确定在这种模式下，急性和长期暴露于可卡因如何影响认知加工，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。目的3将检验可卡因奖励的认知表现的影响，作为动物对选择可卡因和果汁信号试验的偏好的功能。这些分析将在个体动物选择可卡因和果汁试验方面部分排除可卡因的影响，并检查上述三个脑区18FDG脑代谢活动的PET成像差异，以确定在相同的DMS模式下，更喜欢可卡因和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六个月的日常测试中反复暴露于可卡因和食欲奖励以同样随机方式实施的条件下的动物。在这段时间内，DMS对可卡因和果汁奖励的反应（表现）和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的一部分施用的药物的长期有效性。目的4将研究DMS任务中认知需求的上述行为和18FDG成像相关因素如何随着两种候选治疗药物（莫达非尼和下丘脑分泌素-1受体拮拮剂SB334867）的预先治疗而变化，这两种候选治疗药物可以改变可卡因在自我给药范式中的强化作用，目前被认为是人类临床试验中治疗可卡因成瘾的可能化合物。这些药物在试验早期阶段的作用将与长期暴露于同一范式后的效果进行比较，使用性能和偏好测量作为可卡因作用变化与18FDG成像相关改变的指标。

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.