Effect of Drug Sensitization on Phasic Dopamine During Pavlovian Conditioning

描述（由申请人提供）：关于药物成瘾的病因学的一个新兴观点是，在其发展和进展过程中，奖励相关学习和记忆的神经机制存在病理性篡夺。这种“异常学习”假说的支持提供了解剖学，电生理学和生物化学证据的激活假定的分子机制的学习和记忆药物暴露。行为敏感化是反复暴露于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，但也增加了药物和相关线索的激励价值。这些行为效应伴随着丘脑核（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增加了线索的激励显着性，或者在学习过程中充当强化信号。除了致敏作用外，异常习惯的形成和随之产生的对灭绝的抵抗被认为有助于成瘾性疾病。刺激-反应习惯学习被假设严重依赖于背侧纹状体的多巴胺能调节。该项目的总体目标是评估多巴胺在这些现象中的精确贡献，通过监测在NAcb和背侧纹状体中的阶段性多巴胺反应，在条件巴甫洛夫方法对预测奖励的刺激的获取、维持和消退过程中。具体目标1将检查整个学习过程中NAcb和背侧纹状体中的阶段性多巴胺活性。多巴胺将使用快速扫描循环伏安法检测亚秒级的时间分辨率。这将使我们能够解剖对环境的特定成分（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过程中对奖励预测刺激的发展和在消退过程中减少的速率（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，促进了灭绝过程中的持续活动。具体目标2将评估药物致敏对学习期间两个纹状体亚区（纹状体背外侧核与纹状体背外侧核）中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药物未接触过的动物中进行。这些实验将提供新的见解多巴胺传输在学习药物的经验，并提供一个基础，以测试假设异常学习成瘾的基础。

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.