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: 7407223
• 负责人: Jeremy J. Clark
• 金额: $ 4.48万
• 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/7407223
• 关键词: Animals; Behavior; Behavioral; Binding; Biochemical; Chemosensitization; Chronic; Cocaine; Condition; Conditioned Stimulus; Corpus striatum structure; Cues; Development; Disease; 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; Numbers; Pharmaceutical Preparations; Psychological reinforcement; Rate; Resistance; Resolution; Response to stimulus physiology; Rewards; Role; Scanning; Secondary to; Signal Transduction; Stimulus; Structure; Testing; Thinking; 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）：一种关于药物成瘾病因的新观点认为，在其发展和进展过程中，与奖励相关的学习和记忆的神经机制存在病理性篡夺。这种“异常学习”假说得到了解剖学、电生理和生化证据的支持，这些证据证明了药物暴露后学习和记忆的分子机制的激活。行为致敏是反复接触药物的早期后果之一。这包括一些显性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多巴胺释放的神经化学致敏。在这个结构中释放多巴胺被认为增加了线索的激励显著性或作为学习过程中的强化信号。除了致敏，异常的习惯形成和随之而来的对消失的抵抗被认为是导致成瘾性疾病的原因。假设刺激-反应习惯学习严重依赖于背纹状体的多巴胺能调节。这个项目的总体目标是通过监测nnacb和背纹状体在获得、维持和消除条件反射巴甫洛夫方法预测奖励刺激过程中的阶段性多巴胺反应，来评估多巴胺在这些现象中的精确贡献。具体目标1将在学习过程中检查NAcb和背纹状体的阶段性多巴胺活性。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特定环境成分（条件与非条件刺激）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，我们将测试多巴胺反应在获得期间对奖励预测刺激的发展和在消失期间减弱的速率（试验次数）的解剖学差异。据推测，这与背侧纹状体在刺激反应习惯中的选择性作用有关，在灭绝期间促进持续活动。具体目标2将评估药物致敏对学习过程中两个纹状体亚区（伏隔核和背外侧纹状体）的阶段性多巴胺活性的影响。这些实验将在对可卡因过敏的动物和对毒品不熟悉的动物身上进行。这些实验将对多巴胺在吸毒后学习过程中的传递提供新的认识，并为验证异常学习作为成瘾基础的假设提供基础。