Component 8: Zorrilla

第 8 部分：索里拉

基本信息

批准号：
8374917
负责人：
ERIC P ZORRILLA
金额：
$ 19.5万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8374917
关键词：
Abstinence Acute Addictive Behavior Affect Affective Affective Symptoms Alcohol consumption Alcohol withdrawal syndrome Amygdaloid structure Anti-Anxiety Agents Anxiety Behavior Behavioral Brain Brain region Cellular Neurobiology Chronic Corticotropin-Releasing Hormone Data Ethanol Ethanol dependence Funding Immunoassay Individual Intake Lateral Ligands Maintenance Microinjections Modeling Neurobiology Neuropeptide Y Receptor Peptides Property Rattus Recording of previous events Relapse Research Role Self-Administered Septum of Brain Signal Transduction Site Specificity Staging Stress Symptoms System Techniques Testing Time Withdrawal Withdrawal Symptom alcohol abstinence alcohol effect alcohol exposure alcohol reinforcement alcohol research binge drinking design drinking multidisciplinary neuroadaptation neurochemistry neuropeptide Y prevent receptor therapeutic development vapor ward

项目摘要

As ethanol dependence develops, intake transitions from controlled drinking to uncontrolled, compulsive, and excessive intake. Neuroadaptations that result from chronic, heavy ethanol use ("binge-like drinking") are hypothesized to drive this progression, leading to the emergence of relapse-motivating negative affect upon cessation of intake. Ethanol intake thereby becomes compelled for its negative reinforcing properties -- to ward off or relieve affective withdrawal symptoms. Time course studies suggest that acute and late protracted abstinence are distinct stages of withdrawal that motivate drinking and whose neurobiological underpinnings remain unclear. Behavioral and neurochemical data implicate roles for dysregulated extrahypothalamic corticotropin-releasing factor (CRF) and neuropeptide Y (NPY) function in affective withdrawal symptoms. The overarching hypothesis of the present application is that chronic heavy ethanol use leads to increases in anxiogenic extrahypothalamic CRF! or Y2 signaling and decreases in anxiolytic Yi activity, each of which contributes to "passive" anxiety behaviors during protracted ethanol abstinence. SPECIFIC AIM 1 will determine whether a chronic history of self-administered binge drinking leads to increased anxiety-like behavior upon acute or protracted ethanol withdrawal. SPECIFIC AIM 2 will determine whether rats rendered ethanol dependent via chronic passive ethanol vapor exposure or via chronic voluntary binge drinking show similar abnormalities in expression of CRF, NPY or their cognate receptors in components of the central extended amygdala or lateral septum, brain regions that subserve anxiety-like behavior and ethanol reinforcement. Using LC-MS, immunoassay, and quantitative and functional autoradiographic techniques, studies seek to identify which neurochemical changes coincide with the resurgence of anxiety-like behavior observed from early (2 weeks) to late (6-12 weeks) protracted withdrawal. Finally, SPECIFIC AIM 3 microinjects selective CRF and NPY receptor ligands into discrete brain regions to determine the functional relevance of neurochemical changes seen in AIM 2 for the increased anxiety of protracted withdrawal.

随着乙醇依赖的发展，摄入量从控制饮酒转变为不受控制、强迫性和过量摄入。据推测，长期大量使用乙醇（“暴饮暴食”）引起的神经适应会推动这一进展，导致停止摄入后出现诱发复发的负面影响。因此，人们不得不摄入乙醇，因为它具有负面的强化特性——避免或缓解情感戒断症状。时间进程研究表明，急性和晚期长期戒酒是激发饮酒的不同戒断阶段，其神经生物学基础仍不清楚。行为和神经化学数据表明下丘脑外促肾上腺皮质激素释放因子（CRF）和神经肽Y（NPY）功能失调在情感戒断症状中的作用。本申请的总体假设是，长期大量使用乙醇会导致致焦虑的下丘脑外CRF增加！或 Y2 信号传导以及抗焦虑 Yi 活性的降低，这两者都会导致长期戒酒期间的“被动”焦虑行为。具体目标 1 将确定长期自我酗酒史是否会导致急性或长期乙醇戒断后焦虑样行为增加。具体目标 2 将确定大鼠是否通过慢性被动乙醇蒸气暴露或通过长期自愿酗酒而产生乙醇依赖，在中央延伸杏仁核或侧隔膜、促进焦虑样行为的大脑区域中的 CRF、NPY 或其同源受体的表达表现出类似的异常。乙醇强化。使用 LC-MS、免疫分析以及定量和功能放射自显影技术，研究试图确定哪些神经化学变化与从早期（2周）到晚期（6-12周）长期戒断观察到的焦虑样行为再次出现。最后，SPECIFIC AIM 3 将选择性 CRF 和 NPY 受体配体显微注射到离散的大脑区域，以确定 AIM 2 中观察到的神经化学变化与长期戒断焦虑增加的功能相关性。