Motivated Binge and High-Intensity Drinking in Selected Rat Lines

项目总结 要了解狂饮和高强度饮酒(BHID)背后的神经回路，需要一只动物 自愿可靠地表达这一行为的模型。嗜酒P大鼠与高酒 饮酒使大鼠(两种啮齿动物模型都有人类酒精使用障碍家族史；AUD)有 任何酒精暴露前的行为特征表明有两种不同的途径导致AUD：P大鼠是 倾向于发射行为、冲动和增强剂驱动；相比之下，HAD不太可能发射行为， 不冲动，更焦虑。此外，我们的初步数据显示，线条和性别显示 不同的BHID类摄取模式。因此，P和HAD大鼠表现出不同的表型，与 “奖赏”和“解脱”饮酒分别是人类的两种风险表型。这项建议的目的是 识别调节BHID样消耗的特定神经通路中的假想病理 对应于被认为支持奖励和缓解饮酒的回路(前额叶皮质到伏隔核； 前额叶皮质至基底外侧杏仁核)。具体地说，这项建议将利用(I)动物的组合 行为分化AUD风险模型，在该模型中我们(Ii)使用轨迹追踪来揭示关键的差动回路 在字里行间(III)，我们将反过来操纵它来双向驱动行为冲动和 隐藏的行为。该中心组件的意义在于，它将在 调节内表型危险行为的电路的结构和功能(使用停止信号 反应时任务)和酒精寻求和BHID(使用操纵者寻求/饮酒范式)。此外， 从这些发现中，结合IARC的其他项目，我们可能最终了解到潜在的 这些特征导致AUD进展的机制。尤其是在一个“精确”的时代 药物“，其中药物疗效可能取决于不同的基因图谱和饮酒模式，一个 在发育之前，必须先了解不同的、受基因影响的酒精依赖途径 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.