INIA: Stress and Ethanol Self-Administration in Monkeys

描述(由申请人提供)：在“开放获取”条件下评估的乙醇自我给药允许描述慢性乙醇中毒如何将生物体推向超越正常的自我平衡极限(恒定的内部环境)，进入慢性、可变的应激反应(异位反应)和疾病状态。理解压力和过量饮酒之间明显的相互作用关系的一个关键障碍是受试者内部关于神经遗传学、神经化学、神经生理学、神经内分泌和行为对慢性酒精适应的综合、纵向数据集的可用性。自我给予高剂量乙醇20个月的猕猴可以提供这些数据集；最好是在高度协作和整合的环境中，例如酒精中毒综合神经科学倡议(INIA)。因此，在这次更新中，我们将继续在INIA联盟中提供非人类灵长类动物的联系，以解决人类已知(或怀疑)与压力、焦虑和过度饮酒有关的基本方面。我们建议在俄勒冈州国家灵长类动物研究中心(ONPRC)将我们对过量酒精自我给药的纵向适应研究从食蟹猴扩展到恒河猴系种群。这些研究将解决过度饮酒的压力和风险的基本问题，包括紧张性挑衅后的消费模式，以及反复长期戒酒。翻译变量将包括猴子从中度饮酒过渡到重度饮酒时饮酒模式的变化，特定的前额叶皮质表观遗传适应，循环内分泌和肽标记，以及功能连接性磁共振(FcMRl)研究。此外，研究设计还提供了前所未有的机会，以调查与慢性酒精自醉后果相关的整合神经回路关键区域的潜在突触变化。

DESCRIPTION (provided by applicant): The self-administration of ethanol assessed under "open-access" conditions allows the characterization of how chronic ethanol intoxication pushes the organism beyond the normal limits of homeostasis (a constant internal environment) and into chronic, variable, stress responses (allostasis) and disease states. A critical barrier to understanding the apparent reciprocal relationship between stress and excessive ethanol drinking is the availability of within-subject comprehensive, longitudinal data sets on the neurogenetic, neurochemical, neurophysiological, neuroendocrine, and behavioral adaptations to chronic ethanol. The macaque monkey that self-administers high doses of ethanol for >20 months can provide these data sets; optimally within a highly collaborative and integrative environment such as the Integrative Neuroscience Initiative on Alcoholism (INIA). Therefore, in this renewal, we will continue to provide a nonhuman primate link in the INIA consortium to address fundamental aspects of what is known (or suspected) in humans with respect to stress, anxiety and excessive alcohol drinking. We propose to extend our study on longitudinal adaptations to excessive ethanol self-administration from cynomolgus monkeys to the rhesus monkey pedigree population at the Oregon National Primate Research Center (ONPRC). The studies will address fundamental questions of stress and risk for excessive drinking including consumption patterns following stressful provocations and repeated periods of prolonged abstinence from alcohol. Translational variables will include changes in the patterns of drinking alcohol as monkeys transition from moderate to heavy drinking, specific prefrontal cortical epigenetic adaptations, circulating endocrine and peptide markers, and functional connectivity MRI (fcMRl) studies. In addition, the research designs allow for unprecedented opportunities to investigate underlying synaptic changes in key regions of an integrative neural circuitry associated with the consequences of chronic alcohol self-intoxication.