6/8: INIA Stress and Chronic Alcohol Interactions: Stress and Ethanol Self Administration in Monkeys

项目摘要 长期大量饮酒会导致压力平衡的破坏和压力的前馈循环。 酒精与压力的相互作用，进一步加剧了饮酒。恒河猴酒精自我调节模型 研究人员已经记录了与慢性重度酒精相关的关键脑区内的非稳态变化 喝酒这些包括下丘脑控制的应力轴和背侧纹状体（尾状核和壳核） 参与控制动作选择。具体来说，纹状体和HPA轴的神经适应性相关 随着复发期间饮酒的增加，行动选择的灵活性不足， 兴奋-抑制平衡有利于感觉运动神经回路。拟议的研究将利用 压力调节和行为灵活性的个体差异，以确定过度 酗酒和容易复发一体化设计包括：自我管理与重复 恒河猴的戒断/复发周期;行为选择灵活性的纵向测量，压力 利用rs-fMRI研究脑神经回路的反应和完整性;操纵灵长类动物的皮质-背纹状体回路 大脑使用专门由设计药物激活的设计受体（DREADDs）来改变乙醇饮用， 行为灵活性和压力反应。最终，该项目旨在确定皮质-纹状体回路的作用， 保护或促进过量饮酒。这项研究也将有助于新兴的性行为 通过平衡性别设计，研究慢性饮酒的压力反应差异。

PROJECT SUMMARY Chronic, heavy alcohol consumption leads to a disruption of stress homeostasis and a feed-forward cycle of alcohol-stress interactions that further exacerbate alcohol drinking. The rhesus monkey model of alcohol self- administration has documented allostatic changes within key brain areas associated with chronic heavy alcohol drinking. These include hypothalamic control of the stress axis and the dorsal striatum (caudate and putamen) implicated in control of action selection. Specifically, the striatal and HPA axis neuroadaptations were associated with an increase in alcohol drinking during relapse, deficits in flexibility in action selection and shift in the excitatory-to-inhibitory balance favoring the sensorimotor neurocircuitry. The proposed studies will exploit individual differences in stress regulation and behavioral flexibility to identify mechanisms underlying excessive drinking and susceptibility to relapse. The integrative designs encompass: self-administration with repeated abstinence/relapse cycles in rhesus monkeys; longitudinal measures of flexibility in action selection, stress response and integrity of brain neurocircuitry using rs-fMRI; manipulating cortico-dorsostriatal circuits in primate brain using designer receptors exclusively activated by designer drug (DREADDs) to alter ethanol drinking, behavioral flexibility and stress response. Ultimately, this project aims to define the role of cortico-striatal circuitry in protecting or facilitating excessive alcohol drinking. The research will also contribute to emerging sex differences in the stress response to chronic drinking through a balanced sex design.