Role of corticostriatal dopamine signaling in response strategy selection.

描述（由申请人提供）：本提案的主要目的是结合分子，药理学和行为技术来研究皮质纹状体多巴胺信号在反应策略选择中的作用。利用啮齿类动物的工具习惯模型，我们将通过向背外侧纹状体和边缘下皮层的大脑区域注入受体激动剂和拮抗剂，研究多巴胺D1和D2受体的活动如何影响行为，这些区域涉及刺激反应习惯和目标导向行为。此外，我们将研究kappa阿片系统在酒精习惯性和目标导向反应中的作用，该系统已知与酒精相互作用以影响多巴胺信号。根据初步数据，我们假设D1和D2受体的活性会促进不同的反应策略，例如D1会促进习惯性反应，而D2会促进目标导向的行为。此外，我们预计背外侧纹状体中kappa阿片受体活性的增强将通过减少该区域的多巴胺信号传导来促进目标导向行为，而在边缘下皮层中则相反：这里的kappa阿片受体活性将通过减少多巴胺活性来促进习惯性反应。我们假设阻断这些区域的kappa阿片受体活性将产生相反的效果。最后，我们提出，从目标导向行为到习惯性反应的转变将以背外侧纹状体和边缘下皮层中kappa阿片受体活性和表达的变化（通过Western blot分析测量）为特征，并且与接受食物强化的动物相比，接受酒精强化的动物这些变化的时间过程将加快。拟议实验的结果有望为临床研究提供信息，为患有酒精使用障碍的个人开发有效和成功的治疗方法。

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.