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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结