Motivated Binge and High-Intensity Drinking in Selected Rat Lines

项目摘要 了解神经回路的基础狂欢和高强度饮酒（BHID）需要一个动物 一个可靠地表达这种自愿行为的模型。嗜酒P大鼠与高酒精 饮酒HAD大鼠（两种人类酒精使用障碍家族史的啮齿动物模型; AUD） 在任何酒精暴露之前的行为特征表明AUD的两种不同途径： 倾向于发出行为，冲动，和行为驱动;相比之下，HAD不太可能发出行为， 不是冲动，而是焦虑。此外，我们的初步数据显示，线和性别显示， 不同的BHD样摄入模式。因此，P和HAD大鼠表现出不同的表型， “奖励”和“救济”饮酒，分别是人类的两种风险表型。这项建议的目的是 鉴定调节BHID样消耗的特定神经通路中的假设病理， 对应于被认为支持奖励和缓解饮酒的回路（前额叶皮层到核内神经元; 前额皮质到基底外侧杏仁核）。具体而言，该提案将利用以下组合：（i）动物 行为分歧澳元风险模型，其中我们（ii）采用道跟踪，以揭示关键的差分电路 在（iii）线之间，我们将反过来操纵以双向驱动行为冲动和 BHID行为。这个中心组件的意义在于，它将发现关键的新机制， 调节内表型风险行为的电路的结构和功能（使用停止信号 反应时间任务）和酒精寻求和BHID（使用操作性寻求/饮酒范式）。此外，委员会认为， 从这些发现中，结合其他IARC项目，我们最终可能会了解到 这些特征的机制有助于发展为AUD。特别是在一个“精确”的时代， 药物疗效可能取决于不同的遗传特征和饮酒模式， 了解不同的，受遗传影响的酒精依赖途径必须先于发展 有效的AUD治疗。

PROJECT SUMMARY Understanding the neural circuitry that underlies binge and high intensity drinking (BHID) requires an animal model that reliably expresses this behavior voluntarily. The alcohol-preferring P rats and the High Alcohol Drinking HAD rats (both rodent models of a human family history of alcohol use disorder; AUD) have behavioral profiles prior to any alcohol exposure that suggest two different pathways to AUD: the P rats are prone to emit behavior, impulsive, and reinforcer-driven; by contrast the HADs are less likely to emit behavior, not impulsive, and more anxious. In addition, our preliminary data show that the lines and sexes display different BHID-like intake patterns. Therefore, P and HAD rats show distinct phenotypes that correspond with “reward” and “relief” drinking, respectively— two risk phenotypes in humans. The objective of this proposal is to identify hypothesized pathologies in specific neural pathways regulating BHID-like consumption that correspond to circuits thought to support reward and relief drinking (prefrontal cortex to nucleus accumbens; prefrontal cortex to basolateral amygdala). Specifically, this proposal will utilize the combination of (i) animal models of behaviorally divergent AUD risk in which we (ii) employ tract tracing to reveal key differential circuits between the lines (iii) that we will in turn manipulate to bidirectionally drive both behavioral impulsivity and BHID behavior. The significance of this Center Component is that it will discover critical novel mechanisms in the structure and function of the circuitry regulating endophenotypic risk behaviors (using the stop signal reaction time task) and alcohol-seeking and BHID (using the operant seeking/drinking paradigm). Moreover, from these findings, and in conjunction with other IARC projects, we may ultimately learn the underlying mechanisms for these traits that contribute to the progression to an AUD. Particularly in an era of “precision medicine”, where drug efficacy can be dependent upon different genetic profiles and drinking patterns, an understanding of different, genetically-influenced pathways to alcohol dependence must precede development of effective AUD treatment.