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Brain region- and cell-specific roles of CRF-binding protein in alcohol use disorders

CRF结合蛋白在酒精使用障碍中的脑区域和细胞特异性作用

基本信息

批准号：
10057422
负责人：
AUDREY F. SEASHOLTZ
金额：
$ 22.43万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-10 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10057422
关键词：
Abstinence Affect Affinity Alcohol abuse Alcohol consumption Alcohol dependence Alcohols Attenuated Binding Brain region CRF receptor type 1 CRF receptor type 2 CRH gene Cells Chronic Clinical Clinical Research Clinical Trials Cocaine Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors Coupled D Cells Data Dependence Development Disease Dopaminergic Cell Electrophysiology (science)Endocrine Environmental Risk Factor Female G-Protein-Coupled Receptors GTP-Binding Proteins Goals Health Interneurons Ligands Link Medial Mediating Mediator of activation protein Modeling Molecular Mood Disorders Mus Neurons Neurotransmitters Pathway interactions Peptides Pharmacology Play Pre-Clinical Model Prefrontal Cortex Proteins Pyramidal Cells Reagent Reporting Research Rewards Risk Risk Factors Rodent Role Safety Self Administration Sex Differences Signal Pathway Signal Transduction Site Slice Somatostatin Specificity Stress Synapses System Testing Therapeutic Therapeutic Uses Tyrosine 3-Monooxygenase Ventral Tegmental Area Viral alcohol abuse therapy alcohol availability alcohol craving alcohol measurement alcohol relapse alcohol use disorder anxiety-like behavior binge drinking biological adaptation to stress brain cell cell type corticotropin releasing factor-binding protein dependence relapse disability drinking extracellular in vivo inhibitor/antagonist knock-down male new therapeutic target novel therapeutics overexpression pre-clinical preclinical study prevent receptor receptor expression sex small hairpin RNA small molecule social therapeutic target tool virus genetics

项目摘要

Alcohol consumption is the world’s third largest risk factor for disability and disease. Binge alcohol drinking has been linked to many adverse social and health consequences, including an increased risk of transitioning to alcohol dependence. Stress is a key environmental factor in alcohol use and has been linked to alcohol use disorders (AUDs) in clinical and preclinical models. The key CNS regulator of stress is corticotropin-releasing factor (CRF), and CRF plays an important role in modulating binge drinking (BD) and dependence. The CRF system includes two distinct GPCRs, CRF receptor 1 (CRF-R1) and CRF receptor 2 (CRF-R2), and a secreted CRF-binding protein (CRF-BP) that binds CRF with an affinity equal to or greater than the receptors. While CRF and CRF-R1 have been clearly implicated in AUDs, CRF-R1 antagonists have been ineffective in clinical trials. Strikingly, CRHBP SNPs have been associated with BD and dependence, CRF-BP expression is regulated in BD, and rodent pre-clinical studies suggest that blocking CRF-BP activity in VTA may decrease BD. Yet, the functional roles of CRF-BP within the stress/reward pathways and its modulation of CRF receptor activity in vivo are not well understood. Dissecting the specific roles of CRF-BP in different brain regions in binge and heavy alcohol drinking may enable the discovery of new therapeutic treatments to reduce BD and prevent escalation to dependence. Secreted CRF-BP inhibits CRH activity at CRF-R1, while CRF-BP appears to enhance CRF-R2 signaling in VTA; other studies suggest that intracellular CRF-BP acts as an escort protein for CRF-R2. We propose that CRF-BP plays multiple roles, likely in a brain region or cell-type specific manner, with CRF receptor subtype as a potential determinant. In this R21 proposal, we will focus on 2 key interacting sites of CRF-BP/CRF receptor co-expression within the stress/reward pathways, the prefrontal cortex (mPFC) and ventral tegmental area (VTA). Using a combination of pharmacological (CRF6-33 and receptor antagonists), viral, and genetic tools, we will compare the intracellular and extracellular roles of the CRF-BP in the cell types normally expressing CRF-BP in the mPFC and VTA. We will utilize the drinking in the dark (DID) and chronic intermittent access to alcohol (IAA) models to assess the role of CRF-BP across the transition from BD to dependence-like drinking. Both male and female mice will be studied as sex-specific changes in CRF and CRF-R2 expression have recently been reported in BD. We will examine the role of CRF-BP in mPFC (Aim 1) and VTA (Aim 2) using an extracellular CRF-BP antagonist (CRF6-33), viral CRF-BP knockdown, and cre- dependent overexpression of CRF-BP in mPFC sst-expressing cells (Aim 1C) and VTA TH-expressing neurons (Aim 2C). We hypothesize that CRF-BP has largely inhibitory roles at CRF-R1 in PFC, while CRF-BP in VTA may have both inhibitory and enhancing roles via CRF-R1 and CRF-R2 respectively. Results from this project will advance our understanding of brain region and cell-specific roles of CRF-BP, as well as characterize the potential for CRF-BP antagonists as a novel therapeutic target for treatment of AUDs.

酒精消费是导致残疾和疾病的世界第三大风险因素。狂饮酒精