CELLULAR CORRELATES OF COCAINE REINFORCEMENT

本子项目将继续研究非人类灵长类动物的动机和认知的细胞相关性，因为它们与可卡因对不同训练范式下的表现和行为的影响有关。该子项目建立了记录恒河猴从事复杂行为和认知任务时不同脑区单个和多个单个单元活动的方法。第一个任务是Go-Nogo范式，其中果汁和可卡因都被用作强化物，在试验中启动或抑制对特定刺激的反应。在任务中有三种不同的奖励条件，每一种都测试果汁和可卡因奖励反应的不同方面。在训练有素的猴子中，神经元活动从腹侧和背侧纹状体、额叶皮层和黑质/VTA复合体记录下来。在腹侧纹状体区域，我们发现神经元分成不同的类别来编码任务的所有特征，包括编码可卡因作为强化物的实验的特定神经元，而不是那些提供果汁的实验。第二个主要任务是短期记忆的认知测试，其中刺激以延迟匹配样本范式呈现。在匹配阶段，猴子被训练在1-30秒的延迟时间内从2-6个其他刺激中识别一个样本物体。在任务的匹配阶段，延迟时间的长短和可供选择的物品数量都会降低猴子的表现。海马和额叶皮层的神经元被记录下来，果汁或可卡因被作为奖励呈现在试验对试验的基础上。排出模式的变化作为可卡因与果汁强化的函数将被评估。此外，在上述两种行为范式中，长期暴露于可卡因（100天）对具有任务相关放电倾向的神经元的放电模式变化的影响将被评估。在药物奖励试验中，猴子将被隔离30或60天，用生理盐水代替可卡因，以消除与先前任务相关的线索。戒断后，将重新进行可卡因恢复，重新进行药物试验（以及与药物奖励相关的原始刺激）。将评估上述结构中已识别细胞类型的神经元放电模式的变化，以确定长期接触可卡因后系统敏感性的变化。

This subproject will continue to investigate cellular correlates of motivation and cognition in nonhuman primates as they relate to influences of cocaine on performance and behavior under different training paradigms. The subproject has established the means to record single and multiple single unit activity in different brain regions while rhesus macaque monkeys are engaged in complex behavioral and cognitive tasks. The first task is a Go-Nogo paradigm in which both juice and cocaine are utilized as reinforcers for either initiating or withholding responses to specific stimuli within the trial. There are three variations of reward conditions that are employed in the task each testing a different aspect of juice vs cocaine rewarded responding. Neuronal activity is recorded from the ventral and dorsal striatum, frontal cortex and substantia nigra/VTA complex in monkeys that are well trained to perform the tasks. In the ventral striatai area we have found that neurons segregate into distinct classes to encode all the features of the task, including specific neurons that encode trials on which cocaine is the reinforcer and not those trials in which juice is delivered. The second major task is a cognitive test of shortterm memory in which stimuli are presented in a delayed-match-to-sample paradigm. Monkeys are trained to respond to identify a sample object from 2-6 other stimuli in the match phase at delays of 1-30 sec. Performance decreases both as a function of length of delay and number of items to choose from during the match phase of the task. Neurons are recorded from the hippocampal formation and frontal cortex and juice or cocaine presented as rewards on a trial-to- trial basis. Changes in discharge pattem as a function of cocaine vs juice reinforcement will be assessed. In addition, the effects of long-term exposure to cocaine (100 days) in the above two types of behavioral paradigms will be assessed with respect to changes in firing patterns of neurons with task-relevant firing tendencies. Monkeys will be withdrawn for a period of 30 or 60 days and saline delivered instead of cocaine on drug rewarded trials to extinguish prior task-associated cues. After withdrawal, cocaine reinstatement will be implemented in which drug trials (and the original stimuli associated with drug rewards) will be re-invoked. Alterations in neuronal firing patterns of identified cell types in the above structures will be assessed relative to initial exposure to cocaine to determine changes in system sensitivity following long-term exposure.