Prefrontal cortex regulation of ethanol-reinforced behavior

 描述(申请人提供)：许多神经处理流汇聚在前额叶皮质(PFC)，平衡该区域处理的信息的汇流对于调节行为至关重要。这一区域信息的维持和整合主要是通过神经调节驱动的改变而实现的，而且是严重改变的 对于有酒精使用障碍(AUD)的人或那些容易患这种疾病的人。具体地说，调节性神经递质多巴胺(DA)在强化学习、奖赏选择行为的动机方面以及在大鼠和人类的奖赏相关刺激的处理方面都有很强的相关性。考虑到这一点，确定DA等神经调节剂如何调节PFC中的信息传递，以及它们如何因饮酒和过度饮酒风险而改变，是目前尚未得到满足的关键需求。这项研究计划的基本原理是，PFC中DA信号的失衡导致了神经加工的改变，这在酒精在AUD中获得的过度动机特性中起着关键作用。与大脑其他部分相比，前额叶DA的摄取和扩散动力学是独特的，因为它们在很大程度上是由儿茶酚-O-甲基转移酶(COMT)介导的。九项在美国国立卫生研究院注册的临床试验目前正在评估COMT抑制剂托卡彭是否为治疗急性髓细胞白血病的可行选择 一些神经精神障碍，包括药物使用和赌博障碍。然而，这种药物的治疗机制尚不清楚。来自我们小组的初步数据有力地表明，托卡彭抑制过度饮酒的啮齿动物模型中的酒精动机行为。这些数据启发了一系列多学科的实验，以确定托卡彭的作用是否通过PFC DA系统介导，以及这种药物如何改变这一大脑区域的神经处理。具体目标1将确定Tolcapone是否通过PFC DA受体抑制酒精激发的行为。具体目标2将量化COMT中的线条和性别差异，并确定COMT中的适应性变化是否发生在动机行为之后。具体目标3将描述预期和饮酒期间的电生理活动，以确定哪些措施是酒精动机行为所必需的。由于Tolcapone给药会抑制酒精激发的行为，因此它应该干扰这些行为所必需的神经过程。通过这种方式，这些数据将超越生理和行为之间的相关性，并允许在神经活动的变化和酒精驱动的行为之间建立因果关系。

 DESCRIPTION (provided by applicant): A number of neural processing streams converge in the prefrontal cortex (PFC), and balancing the confluence of information processed by this region is critical for regulating behavior. The maintenance and integration of information in this region is primarily achieved through alterations in neuromodulatory drive and is critically altered in individuals with an alcohol use disorder (AUD) or those vulnerable to this condition. Specifically, the modulatory neurotransmitter dopamine (DA) has been strongly implicated in the motivational aspects of reinforcement learning, reward choice behavior, and in processing of reward-related stimuli in both rats and humans. Considering this, identifying how neuromodulators, such as DA, mediate information transfer in the PFC and how they are altered as a consequence of alcohol drinking and in those at risk for excessive drinking represents a currently unmet and critical need. The rationale of this research plan is that imbalanced DA signaling in the PFC leads to alterations in neural processing, which plays a key role in the excessive motivational properties acquired by alcohol in AUD. The uptake and diffusion kinetics of DA in the PFC are unique compared with the rest of the brain, in that they are largely mediated by the enzyme catechol-O-methyl- transferase (COMT). Nine NIH-registered clinical trials are currently assessing if the COMT inhibitor, Tolcapone, is a viable treatment option for a number of neuropsychiatric disorders, including substance use and gambling disorders. However, a clear therapeutic mechanism of this drug has not been identified. Preliminary data from our group strongly indicates that Tolcapone suppresses alcohol-motivated behaviors in a rodent model of excessive drinking. These data inspired a multidisciplinary set of experiments to determine if the effects of Tolcapone are mediated via the PFC DA system and how this drug alters neural processing in this brain region. Specific Aim 1 will determine if Tolcapone suppresses alcohol-motivated behaviors through PFC DA receptors. Specific Aim 2 will quantify line and sex differences in COMT and determine if adaptive changes in COMT occur following motivated behavior. Specific Aim 3 will characterize electrophysiological activity during anticipation and drinking to identify which measures are necessary for alcohol-motivated behaviors. Since Tolcapone administration will suppress alcohol-motivated behaviors it should therefore interfere with the neural processes necessary for them. In this way, these data will move beyond correlations between physiology and behavior and allow causal relationships to be established between changes in neural activity and alcohol-motivated behaviors.