Impact of prenatal opioid exposure on corticostriatal circuits that modulate alcohol-related behaviors

产前阿片类药物暴露对调节酒精相关行为的皮质纹状体回路的影响

• 批准号: 10708335
• 负责人: Brady Atwood
• 金额: $ 58.56万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-16 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708335
• 关键词: AMPA Receptors; Ablation; Abstinence; Address; Affect; Alcohol abuse; Alcohol consumption; Alcohols; Anatomy; Anterior; Award; Behavioral; Biochemical; Birth; Brain; Brain region; Child; Clinical; Clinical Research; Confocal Microscopy; Corpus striatum structure; Data; Dorsal; Electrophysiology (science); Exposure to; Female; Fetal Tissues; Future; Glutamates; Grant; Heavy Drinking; Home; Incidence; Individual; Institution; Interneurons; Knowledge; Label; Laboratories; Literature; Long-Term Depression; Measurement; Measures; Mediating; Methadone; Microscopy; Modeling; Molecular; Morbidity - disease rate; Mothers; Mus; N-Methyl-D-Aspartate Receptors; Neonatal; Neurons; Opiate Addiction; Pathway Analysis; Pathway interactions; Phosphorylation; Physiological; Population; Predisposition; Pregnant Women; Prevalence; Proteins; Proteome; Proteomics; Recording of previous events; Replacement Therapy; Reporter; Resistance; Rewards; Role; Saline; Shapes; Slice; Source; Sucrose; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Time; Water; Work; alcohol behavior; alcohol effect; alcohol exposure; alcohol response; alcohol use disorder; behavioral response; binge drinking; cell type; clinically relevant; density; drinking; drinking behavior; experience; fetal opioid exposure; in vivo; insight; interdisciplinary approach; male; mortality; mouse model; neural; novel; offspring; opioid exposure; opioid misuse; opioid use; opioid use disorder; opioid use in pregnancy; opioid withdrawal; optogenetics; phosphoproteomics; postsynaptic; preclinical study; prenatal; prenatal exposure; prenatal testing; prescription opioid; presynaptic; receptor function; resilience; response; standard of care; stimulant misuse; substance misuse; substance use; synaptic function; synaptic inhibition; synergism; transmission process; wireless

Project Summary The number of children born to opioid-dependent mothers has increased over 300% in the past two decades. As abstinence from opioids during pregnancy is not recommended, opioid medication replacement therapy, such as methadone, represents the standard of care for pregnant women with opioid use disorder thus perpetuating the birth of these opioid-exposed babies. Previous work has shown that prenatal opioid exposure predisposes for future substance misuse. Given its widespread accessibility, alcohol is one of the most likely addictive sub- stances that these prenatal opioid-exposed children will encounter. Due to the significant morbidity and mortality associated with excessive alcohol drinking, it is critically important to understand how prenatal methadone ex- posure (PME) predisposes these children for future problematic alcohol use and how alcohol interacts with PME to produce differential behavioral responses to alcohol. To elucidate mechanisms related to how PME may pro- duce enhanced alcohol-related behaviors, we developed and validated a mouse model of PME. Our model re- capitulates many clinical features of prenatal opioid exposure, including producing neonatal opioid withdrawal. Using our model, we find that PME increases alcohol drinking only in males, consistent with many clinical and preclinical studies that show that males are more severely impacted by prenatal opioid exposure. Given the role of the dorsal striatum brain region in modulating many aspects of alcohol drinking, we biochemically explored the proteome of the dorsal striatum and found that PME had a greater effect on protein and protein phosphory- lation expression in males than females, consistent with our drinking data. Pathway analyses of our proteomics data implicated glutamate and long-term synaptic depression plasticity (LTD) in the dorsolateral striatum (DLS) as being disrupted by PME. We further discovered that PME reduced dorsal striatal glutamate transmission and disrupted LTD. Recent work from our laboratory demonstrates that alcohol induces glutamatergic synaptic plas- ticity and disrupts LTD at anterior insular cortex inputs to the DLS (AICDLS synapses) in mice, but only in male mice and this was associated with enhanced male alcohol drinking behavior. We reasoned that the male-specific, PME-induced increase in binge-like alcohol consumption may utilize similar mechanisms as the male-specific, alcohol-induced AICDLS synaptic changes that govern excessive alcohol consumption. We hypothesize that PME produces synaptic adaptations exclusively in males that enhance AICDLS glutamatergic transmission that in turn govern the elevated binge-like alcohol consumption seen in male, but not female PME mice. In this project we will use a multidisciplinary approach combining home-cage binge drinking with brain slice electro- physiology, dorsal striatal cell type reporter mice, quantitative synaptic proteomics, ultrastructural expansion mi- croscopy, and wireless in vivo optogenetic manipulations of synaptic transmission. This project will provide crit- ical neural mechanistic knowledge for deciphering how PME enhances future alcohol drinking behavior in males and why females may be resistant or resilient to the effects of PME.

项目摘要 在过去二十年中，阿片类药物依赖母亲所生子女的数量增加了300%以上。 由于不建议在怀孕期间戒断阿片类药物， 作为美沙酮，代表了对患有阿片类药物使用障碍的孕妇的护理标准， 这些暴露于阿片类药物的婴儿的出生。先前的研究表明，产前阿片类药物暴露易使 以防止未来的物质滥用。鉴于其广泛的可及性，酒精是最有可能上瘾的亚- 这些产前暴露于阿片类药物的孩子会遇到的情况。由于发病率和死亡率很高， 与过量饮酒有关，了解产前美沙酮如何消除 PME（PME）倾向于这些儿童未来有问题的酒精使用以及酒精如何与PME相互作用 对酒精产生不同的行为反应。为了阐明PME如何促进 诱导增强的酒精相关行为，我们开发并验证了PME小鼠模型。我们的模型- 结论：产前阿片类药物暴露的许多临床特征，包括产生新生儿阿片类药物戒断。 使用我们的模型，我们发现PME只会增加男性的饮酒量，这与许多临床和实验结果一致。 临床前研究表明，男性受到产前阿片类药物暴露的影响更严重。考虑到 背侧纹状体脑区在调节饮酒的许多方面，我们生物化学探索 背侧纹状体的蛋白质组，发现PME对蛋白质和蛋白质磷酸化有更大的影响， 在男性中的表达高于女性，与我们的饮酒数据一致。蛋白质组学的途径分析 数据暗示背外侧纹状体（DLS）中的谷氨酸和长时程突触抑制可塑性（LTD） 被PME破坏。我们进一步发现，PME减少背侧纹状体谷氨酸传输， 我们实验室的最新研究表明，酒精诱导突触能突触体， 在小鼠中，在前岛叶皮层输入DLS（AIC-DLS突触）的活性和破坏LTD，但仅在雄性中 这与增强的男性饮酒行为有关。我们推断，男性特有的， PME诱导的酗酒增加可能利用与男性特异性， 酒精诱导的AIC抑制DLS突触变化，控制过度饮酒。我们假设 PME仅在男性中产生突触适应，增强AIC-DLS谷氨酸能传递 这反过来又控制了在雄性PME小鼠中观察到的升高的狂欢式酒精消耗，而不是雌性PME小鼠。在这 我们将使用多学科的方法，结合家庭笼狂饮与脑切片电， 生理学，背侧纹状体细胞型报告小鼠，定量突触蛋白质组学，超微结构扩展， 显微镜检查和突触传递的无线体内光遗传学操纵。该项目将提供关键- 解释PME如何增强男性未来饮酒行为的神经机制知识 以及为什么女性可能对PME的影响有抵抗力或弹性。