Effect of Drug Sensitization on Phasic Dopamine During Pavlovian Conditioning

巴甫洛夫条件反射过程中药物敏化对阶段性多巴胺的影响

• 批准号: 7559642
• 负责人: Jeremy J. Clark
• 金额: $ 4.72万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7559642
• 关键词: Animals; Behavior; Behavioral; Binding; Biochemical; Chemosensitization; Chronic; Cocaine; Conditioned Stimulus; Corpus striatum structure; Cues; Development; Dopamine; Dorsal; Drug Addiction; Drug Exposure; Drug Sensitization; Drug usage; Environment; Etiology; Extinction (Psychology); Food; Foundations; Goals; Habits; Incentives; Learning; Locomotion; Maintenance; Memory; Molecular; Monitor; N-Methylaspartate; Nucleus Accumbens; Pharmaceutical Preparations; Psychological reinforcement; Resistance; Resolution; Response to stimulus physiology; Rewards; Role; Scanning; Secondary to; Signal Transduction; Stimulus; Structure; Testing; Training; Ventral Striatum; Ventral Tegmental Area; addiction; base; behavioral sensitization; classical conditioning; experience; habit learning; insight; neurochemistry; neuromechanism; psychostimulant; research study; response; trait; transmission process

DESCRIPTION (provided by applicant): An emerging view on the etiology of drug addiction is that during its development and progression there is pathological usurpation of neural mechanisms of reward-related learning and memory. Support for this "aberrant learning" hypothesis is provided by anatomical, electrophysiological and biochemical evidence for the activation of putative molecular mechanisms of learning and memory following drug exposure. Behavioral sensitization is one early consequence of repeated drug exposure. This includes experience dependent potentiation of some overt behaviors, but also an increase in the incentive value of drugs and associated cues. These behavioral effects are accompanied by neurochemical sensitization of dopamine release in the nucleus accumbens (NAcb). Dopamine release in this structure is thought to increase the incentive salience of cues or act as a reinforcement signal during learning. In addition to sensitization, aberrant habit formation and a consequent resistance to extinction are thought to contribute to addictive disorders. Stimulus-response habit learning is hypothesized to rely heavily upon the dopaminergic modulation of the dorsal striatum. The overall goal of this project is to assess the precise contribution of dopamine in these phenomena by monitoring phasic dopamine responses in the NAcb and dorsal striatum during the acquisition, maintenance and extinction of conditioned pavlovian approach to stimuli that predict reward. Specific aim 1 will examine phasic dopamine activity in the NAcb and dorsal striatum throughout learning. Dopamine will be detected with subsecond temporal resolution using fast-scan cyclic voltammetry. This will allow us to dissect the neurochemical responses to specific components of the environment (conditioned vs. unconditioned stimuli) and to detect potential quantitative and/or qualitative differences in the dopaminergic response between the two structures. In particular, we will test for anatomical differences in the rates (number of trials) that dopamine responses develop to reward-predicting stimuli during acquisition and diminish during extinction. This is hypothesized to correlate with a selective role for the dorsolateral striatum in stimulus-response habits, promoting persistent activity during extinction. Specific aim 2 will assess the influence of drug sensitization on phasic dopamine activity in the two striatal subregions (nucleus accumbens vs. dorsolateral striatum) during learning. These experiments will be conducted in animals that have been sensitized to cocaine and in those that are naive to the drug. These experiments will provide new insight into dopamine transmission during learning following drug experience, and provide a foundation to test hypotheses on aberrant learning as a basis for addiction.

描述（由申请人提供）：关于药物成瘾病因学的一种新兴观点是，在药物成瘾的发展和进展过程中，与奖赏相关的学习和记忆的神经机制存在病理性侵占。解剖学、电生理学和生化证据为这种“异常学习”假说提供了支持，这些证据表明药物暴露后学习和记忆的假定分子机制被激活。行为过敏是反复接触药物的早期后果之一。这包括一些明显行为的经验依赖性增强，但也包括药物和相关线索的激励价值的增加。这些行为效应伴随着伏隔核（NAcb）中多巴胺释放的神经化学敏化。这种结构中的多巴胺释放被认为可以增加线索的激励显着性或在学习过程中充当强化信号。除了致敏之外，异常的习惯形成和随之而来的对消除的抵抗被认为会导致成瘾性疾病。假设刺激反应习惯学习在很大程度上依赖于背侧纹状体的多巴胺能调节。该项目的总体目标是通过监测 NAcb 和背侧纹状体在获得、维持和消退预测奖励的条件巴甫洛夫方法期间的阶段性多巴胺反应，评估多巴胺在这些现象中的精确贡献。具体目标 1 将检查整个学习过程中 NAcb 和背侧纹状体的阶段性多巴胺活动。使用快速扫描循环伏安法以亚秒时间分辨率检测多巴胺。这将使我们能够剖析对环境特定成分（条件刺激与非条件刺激）的神经化学反应，并检测两种结构之间多巴胺能反应的潜在定量和/或定性差异。特别是，我们将测试多巴胺在获得过程中对奖赏预测刺激产生反应并在消退过程中减弱的速率（试验次数）的解剖学差异。据推测，这与背外侧纹状体在刺激反应习惯中的选择性作用有关，促进灭绝期间的持续活动。具体目标 2 将评估学习过程中药物致敏对两个纹状体亚区域（伏隔核与背外侧纹状体）阶段性多巴胺活性的影响。这些实验将在对可卡因敏感的动物和对该药物不熟悉的动物中进行。这些实验将为药物体验后学习过程中的多巴胺传递提供新的见解，并为检验作为成瘾基础的异常学习假设提供基础。

项目成果

Dopamine encoding of Pavlovian incentive stimuli diminishes with extended training.

• DOI: 10.1523/jneurosci.5119-12.2013
• 发表时间: 2013-02-20
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Clark JJ;Collins AL;Sanford CA;Phillips PE
• 通讯作者: Phillips PE