Behavioral Endophenotypes for Differential Ethanol-Seeking and Drinking

项目摘要：不同乙醇寻求和饮酒的行为内表型（BESD） I-ARC的一系列研究结果表明， 啮齿动物代表了酒精中毒风险的不同遗传和行为模型。而P和HAD 2大鼠 是高饮酒者，只有P大鼠表现出不良的冲动控制和极端乙醇（EtOH）寻求行为 （Beckwith & Czachowski，2014; 2016）。新的初步数据进一步表明，EtOH naïp大鼠也不同， 从HAD 2大鼠在其对非EtOH甜味剂的快速习惯形成（持续寻求一种新的调味剂）中， 即使在贬值后也是如此）。从概念上讲，习惯的形成表明人们对 尽管有不良后果，但饮酒时的行为结果（抗厌恶性饮酒; ARD） 表明对厌恶刺激的不敏感性与强化配对，两者都是 行为可接受性关于ARD，当EtOH消耗本身对厌恶性反应不敏感时， 结果，个人可能有发展更极端，强迫性饮酒的风险。因此有 迫切需要了解ARD发展的不同行为和神经生物学途径。 的 这一建议的中心假设是，有不同的遗传和行为路径，以强迫 饮酒和我们的长期目标是了解行为能力和乙醇之间的关系， 寻求和饮酒，以开发针对风险表型的药物干预措施， 控制或预防强迫性饮酒的方法。本申请的目的是：1）扩大 在两种动物中，在选定的大鼠品系中鉴定出习惯形成和ARD的独特风险内表型。 性别，以及2）确定这些遗传系的潜在神经回路功能的差异 和行为。 我们提出的工作的积极影响是理解遗传的能力， 行为和神经生物学因素，有助于ARD的发展，当酒精中毒成为 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.