Role of corticostriatal dopamine signaling in response strategy selection.

皮质纹状体多巴胺信号在反应策略选择中的作用。

基本信息

批准号：
8153113
负责人：
JACQUELINE M BARKER
金额：
$ 4.22万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8153113
关键词：
Agonist Alcoholism Alcohols Animals Behavior Behavioral Behavioral Genetics Brain region Chronic Clinical Research Cognitive Consumption Corpus striatum structure Data Decision Making Development Dopamine Dopamine D1 Receptor Dopamine D2 Receptor Dopamine Receptor Dorsal Drug usage Food Functional disorder Genetic Techniques Goals Habits Heavy Drinking Individual Infusion procedures Long-Term Potentiation Measures Mediating Molecular Molecular Genetics Morale N-Methyl-D-Aspartate Receptors Opioid Opioid Peptide Opioid Receptor Outcome Pharmaceutical Preparations Play Prefrontal Cortex Property Receptor Activation Receptor Signaling Reporting Response to stimulus physiology Rewards Rodent Model Role Signal Transduction Societies Stimulus System Techniques Time Training Ventral Striatum Western Blotting alcohol effect alcohol exposure alcohol reinforcement alcohol reward alcohol use disorder base craving dopamine system drinking drug reward flexibility kappa opioid receptors male motivated behavior neurobiological mechanism neurotransmission premature problem drinker public health relevance receptor recidivism reinforcer research study response restoration reward processing therapy design

项目摘要

DESCRIPTION (provided by applicant): The main objective of this proposal is to combine molecular, pharmacological, and behavioral techniques to investigate the role of corticostriatal dopamine signaling in response strategy selection. Using a rodent model of instrumental habit, we will investigate how behavior is influenced by activity at dopamine D1 and D2 receptors in the dorsolateral striatum and infralimbic cortex, brain regions implicated in stimulus- response habit and goal-directed behavior by infusing receptor agonists and antagonists into these regions. Additionally, we will investigate the role of the kappa opioid system, which is known to interact with alcohol to influence dopamine signaling, in habitual and goal-directed responding for alcohol. We hypothesize based on preliminary data that activity at the D1 and D2 receptors will promote differential response strategies, such that D1 will promote habitual responding and D2 activity will promote goal-directed actions. Additionally, we expect that enhanced kappa opioid receptor activity in the dorsolateral striatum will promote goal-directed behavior by decreasing dopamine signaling in this region, while the converse will be true in the infralimbic cortex: kappa opioid receptor activity here will promote habitual responding by decreasing dopamine activity. We hypothesize that blocking kappa opioid receptor activity in these regions will produce the opposite effects. Finally, we propose that the transition from goal-directed actions to habitual responding will be characterized by changes in kappa opioid receptor activity and expression (as measured by Western blot analyses) in the dorsolateral striatum and infralimbic cortex, and that the time course of these changes will be accelerated in animals receiving alcohol reinforcement as compared to those receiving food reinforcers. The findings of the proposed experiments are expected to help inform clinical research move toward developing efficient and successfully therapies for individuals suffering from alcohol use disorders. PUBLIC HEALTH RELEVANCE: Alcohol use disorders are devastating not only to the individuals struggling with alcoholism, but also to society as a whole. As alcoholics transition from casual drug use to compulsive, habitual drug seeking, they show signs of cognitive-motivational dysfunction, resulting in altered reward processing and decision-making that can have highly maladaptive consequences, including heavy drinking, recidivism, risky reward- motivated behaviors, craving and difficultly in terminating consumption. By understanding how the dopamine system interacts with alcohol to influence habitual drug seeking and taking, we can begin to understand neurobiological mechanisms of behavioral flexibility and identify possible therapies for alcohol use disorders that target the restoration of goal-directed behaviors.

描述（由申请人提供）：该提案的主要目的是结合分子，药理和行为技术，以研究皮质纹状体多巴胺信号在响应策略选择中的作用。使用啮齿动物习惯的啮齿动物模型，我们将研究如何在背外侧纹状体和额叶皮层中在多巴胺D1和D2受体上的活性影响行为，大脑区域与刺激反应习惯有关，并通过吸收受体激动剂和拮抗剂进入这些区域。此外，我们将研究Kappa阿片类系统的作用，Kappa阿片类药物与酒精相互作用以影响多巴胺信号传导，以习惯性和目标指导的酒精反应。我们根据初步数据假设，D1和D2受体的活动将促进差异反应策略，以便D1将促进习惯性响应，而D2活动将促进目标指导的行动。此外，我们预计背外侧纹状体中的Kappa阿片受体活性增强，将通过减少该地区的多巴胺信号传导来促进目标指导的行为，而在Infralimbic Cortex：Kappa阿片类受体活性中，相反的情况将是正确的，此处将通过降低多巴胺活性来促进习惯反应。我们假设阻止这些区域中的Kappa阿片类药物受体活性会产生相反的影响。最后，我们建议，从目标指导的行动到习惯反应的过渡将以背侧纹状体和额叶皮层中的Kappa阿片受体活性和表达的变化（通过蛋白质印迹分析进行衡量）的变化，以及这些变化的时间将在这些变化的过程中与这些接收食品相比，这些变化的时间将加速。预计该提议的实验的发现将有助于为临床研究促进为患有饮酒障碍的人开发有效且成功疗法的临床研究。公共卫生的相关性：饮酒障碍不仅毁灭了与酒精中毒斗争的人，而且对整个社会也造成了毁灭性的灾难。随着酗酒者从休闲毒品的使用过渡到强迫性，习惯性毒品，它们显示出认知动机动机功能障碍的迹象，从而改变了奖励加工和决策的改变，可能会带来严重的适应性后果，包括重型饮酒，累犯，风险的奖励行为，渴望和终止消费。通过了解多巴胺系统如何与酒精相互作用以影响习惯性药物寻求和服用，我们可以开始理解行为灵活性的神经生物学机制，并确定针对恢复目标定向行为的酒精使用障碍的可能疗法。