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

项目总结 长期大量饮酒会导致压力稳态的破坏和前馈循环 酒精与压力的相互作用，进一步加剧了饮酒。酒精自我调节的恒河猴模型 管理部门已经记录了与慢性重度酒精相关的关键脑区的变态变化 喝酒。这包括下丘脑对应力轴和背侧纹状体(尾状核和壳核)的控制。 牵涉到对动作选择的控制。具体地说，纹状体和hpa轴的神经适应是相关的。 随着复发期间饮酒的增加，在行动选择和转移中的灵活性不足 兴奋性与抑制性的平衡有利于感觉运动神经回路。拟议中的研究将利用 在压力调节和行为灵活性方面的个体差异，以确定导致过度行为的机制 酗酒和复发的易感性。一体化设计包括：自我管理和重复 恒河猴戒断/复发周期；行为选择灵活性的纵向测量，应激 RS-fMRI对脑神经回路的反应和完整性灵长类动物操纵皮质-背侧纹状体回路 大脑使用由特制药物(DREADDS)独有激活的特制受体来改变酒精饮酒， 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。 在保护或促进过度饮酒方面。这项研究还将对新兴的性行为做出贡献 通过平衡性设计对长期饮酒的压力反应的差异。

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.