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、药理学和行为学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。使用工具习惯的啮齿动物模型，我们将通过向这些区域注入受体激动剂和拮抗剂，来研究纹状体背外侧和下缘皮质中多巴胺D1和D2受体的活性如何影响行为，这些区域是与刺激反应习惯和目标导向行为有关的大脑区域。此外，我们还将研究kappa阿片系统在习惯性和目标导向的酒精反应中的作用，该系统已知与酒精相互作用，影响多巴胺信号转导。基于初步数据，我们假设，D1和D2受体的活性将促进不同的反应策略，即D1将促进习惯性反应，D2活性将促进目标导向的行动。此外，我们预计，纹状体背外侧区kappa阿片受体活性的增强将通过减少该区域的多巴胺信号转导来促进目标定向行为，而在边缘下皮质则相反：这里的kappa阿片受体活性将通过降低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，从目标导向的行动到习惯性反应的转变将以背外侧纹状体和下缘皮质中kappa阿片受体活性和表达的变化(通过Western印迹分析)为特征，并且与接受食物强化剂的动物相比，接受酒精强化的动物的这些变化的时间进程将被加速。拟议中的实验结果有望帮助临床研究为患有酒精使用障碍的个人开发有效且成功的治疗方法。 公共卫生相关性：酒精使用障碍不仅对与酒精中毒作斗争的个人，而且对整个社会都是毁灭性的。随着酗酒者从偶尔吸毒转变为强迫性、习惯性的吸毒，他们表现出认知动机功能障碍的迹象，导致奖赏处理和决策的改变，这可能会产生高度不适应的后果，包括酗酒、累犯、危险的奖赏动机行为、渴望和难以终止消费。通过了解多巴胺系统如何与酒精相互作用来影响习惯性的药物寻求和服用，我们可以开始了解行为灵活性的神经生物学机制，并找到针对酒精使用障碍的可能治疗方法，其目标是恢复目标定向行为。

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.