Behavioral Endophenotypes for Differential Ethanol-Seeking and Drinking

项目概述：不同饮酒和饮酒行为的内表型 来自I-ARC的一系列研究结果表明，选定的酒精品系更倾向于 啮齿动物代表了酒精中毒风险的不同遗传和行为模式。而P和HAD2大鼠 都是酗酒者，只有P鼠表现出较差的冲动控制和极端酒精(Etoh)寻求行为 (Beckwith&Chachowski，2014；2016)。新的初步数据进一步表明，Etoh naive P大鼠也不同 从HAD2大鼠快速形成对非乙醇增强剂的习惯(对一种新口味的不懈追求 解决方案，即使在贬值之后也是如此)。从概念上讲，习惯的养成表明人们对 不顾不良后果饮酒时的行为结果(抗厌恶饮酒；ARD) 表示对厌恶刺激和强化刺激特别不敏感，两者都是 行为僵化。关于ARD，当乙醇消费本身对厌恶变得不敏感时 后果，个人可能面临发展成更极端、强迫性饮酒的风险。因此，有一个 迫切需要了解ARD发展的不同行为和神经生物学途径。这个 这一建议的中心假设是强迫症有不同的遗传和行为途径 我们的长期目标是了解行为不灵活和酒精之间的关系。 寻求和饮酒，以开发针对危险表型的药物干预措施 控制或防止强迫性饮酒的方法。此应用程序的目标是：1)扩展 所选大鼠品系中与习性形成和ARD相关的独特危险内表型的鉴定 性别，以及2)决定这些遗传系潜在神经回路功能的差异 和行为。我们提议的工作的积极影响是能够理解基因， 当酒精中毒变成ARD时，导致ARD的行为和神经生物学因素 更难治疗。通过了解这些因素，我们可以更好地了解如何制定适当的 干预措施。

Project Summary: Behavioral Endophenotypes for Differential Ethanol-Seeking and Drinking (BESD) A body of findings from the I-ARC converges in suggesting that the selected lines of alcohol preferring rodents represent different genetic and behavioral models of alcoholism risk. While both the P and HAD2 rats are high drinkers, only P rats show poor impulse control and extreme ethanol (EtOH)-seeking behaviors (Beckwith & Czachowski, 2014; 2016). New preliminary data further show that EtOH naïve P rats also differ from HAD2 rats in their rapid habit formation for a non-EtOH reinforcer (persistent seeking of a novel flavored solution, even after its devaluation). Conceptually, habit formation indicates a general decreased attention to the outcomes of behavior while drinking despite adverse consequences (aversion-resistant drinking; ARD) indicates insensitivity specifically to aversive stimuli paired with reinforcement, and both are types of behavioral inflexibility. With regard to ARD, when EtOH consumption itself becomes insensitive to aversive consequences, individuals may be at risk for developing more extreme, compulsive drinking. There is thus a critical need to understand the varied behavioral and neurobiological paths by which ARD develops.  The central hypothesis of this proposal is that there are different genetic and behavioral paths to compulsive drinking and our long-term goal is to understand the relationship between behavioral inflexibility and EtOH- seeking and drinking in order to develop pharmacological interventions that target the risky phenotypes as a way to control or prevent compulsive drinking. The objectives of this application are to: 1) expand the identification of the unique risk endophenotypes to habit formation and ARD in the selected rat lines in both sexes, and 2) determine the differences in functionality of the underlying neural circuity of these genetic lines and behaviors.  The positive impact of our proposed work is the capacity to understand the genetic, behavioral, and neurobiological factors that contribute to the development of ARD, when alcoholism becomes harder to treat. By understanding these factors, we can better understand how to develop appropriate interventions.