Alcohol Vapor Self-Administration in Rats

大鼠酒精蒸气自我管理

基本信息

批准号：
8841642
负责人：
Olivier George
金额：
$ 41.36万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8841642
关键词：
Address Affective Alcohol consumption Alcohol dependence Alcohol withdrawal syndrome Alcoholism Alcohols Amygdaloid structure Animal Model Blood Blood alcohol level measurement Brain Brain Mapping Brain region Cannabis Chronic Cocaine Corticotropin-Releasing Hormone Data Dependence Development Diet Dose Exposure to FDA approved Face Gene Expression Glutamates Health Heroin Hour Human Immediate-Early Genes Intoxication Investigation Laboratories Liquid substance Maintenance Measurement Measures Mediating Methamphetamine Modeling Motivation Naltrexone Neurons Nicotine Pharmaceutical Preparations Population Prefrontal Cortex Rattus Recruitment Activity Role Self Administration Self-Administered Techniques Testing Time Toluene Validation Withdrawal Withdrawal Symptom acamprosate alcohol abstinence alcohol availability alcohol exposure alcohol measurement alcohol testing alcoholism therapy animal model development base binge drinking clinically relevant drug of abuse gamma-Aminobutyric Acid neurobiological mechanism novel novel therapeutic intervention pre-clinical research prevent problem drinker research study small molecule vapor

项目摘要

DESCRIPTION (provided by applicant): A major issue in the alcohol field is the lack of animal models of the voluntary induction and maintenance of alcohol dependence, considerably hindering the discovery of the neurobiological mechanisms underlying voluntary intoxication to the point of dependence. While rats will readily self-administer alcohol, the amount of alcohol consumed is very low (typically 10-90 mg% for less than 1 h per day) and therefore do not produce blood alcohol levels that are clinically relevant for alcoholism (100-200 mg% for several hours per day). Other paradigms have been developed to produce alcohol dependence in rats, but these models use either forced or passive exposure to a high dose of alcohol, thus preventing the investigation of the neurobiological mechanisms that underlie the voluntary induction and maintenance of alcohol dependence. The current application directly addresses this issue. We recently developed a novel apparatus that allows rats to self- administer alcohol vapor. We obtained evidence that outbred rats will self-administer alcohol vapor for 12+ h per day to the point of reaching blood alcohol levels in the 100-200 mg% range. We propose to characterize and develop a novel animal model of the voluntary induction and maintenance of alcohol dependence using alcohol vapor self-administration in rats and use brain mapping techniques to identify the neuronal networks mediating the voluntary (vs. forced) induction and maintenance of alcohol dependence. We recently demonstrated that prefrontal cortex neurons producing GABA and corticotropin-releasing factor (CRF) are recruited during withdrawal from alcohol binge drinking, but the role of these neurons in the voluntary induction of alcohol dependence is unknown. The current application will directly test the hypothesis that GABA and CRF neurons in the prefrontal cortex are recruited during the voluntary (vs. forced) induction and maintenance of alcohol dependence. Results from these studies have the potential to radically change preclinical research on alcoholism and may pave the ground for the development of animal models of vapor self-administration for other drugs of abuse, such as cannabis, cocaine, nicotine, methamphetamine, or toluene. Moreover, the proposed set of studies has the potential to unveil neuronal targets specifically recruited during the voluntary (v. passive) induction of alcohol dependence that could be useful for the development of novel therapeutic approaches.

描述（由申请人提供）：酒精领域的一个主要问题是缺乏自愿诱导和维持酒精依赖性的动物模型，从而极大地阻碍了自愿中毒基于的神经生物学机制的发现。虽然大鼠很容易自动饮酒，但消耗的酒精含量非常低（通常每天小于1小时的10-90 mg％），因此不产生与酒精中毒在临床上相关的血液酒精水平（每天几个小时为100-200 mg％）。已经开发出其他范式在大鼠中产生酒精依赖性，但是这些模型使用强制或被动暴露于高剂量的酒精，从而阻止了对自愿诱导和维持酒精依赖的神经生物学机制的研究。当前的应用程序直接解决了此问题。我们最近开发了一种新型设备，使大鼠可以自我施用酒精蒸气。我们获得了证据表明，近代大鼠每天会自动饮酒12+ h，以达到100-200 mg％范围内血液酒精水平。我们建议使用酒精蒸气在大鼠中自愿诱导和维持酒精依赖性的新型动物模型，并使用大脑映射技术来识别介导自愿（强迫）诱导和维持酒精依赖性的神经元网络。我们最近证明，产生GABA和皮质激素释放因子（CRF）的前额叶皮质神经元在退出酒精暴饮暴食期间被募集，但是这些神经元在自愿诱导酒精依赖性中的作用尚不清楚。当前的应用将直接检验以下假设：在自愿（强迫）诱导和维持酒精依赖性期间募集前额叶皮层中的GABA和CRF神经元。这些研究的结果有可能对酒精中毒的临床前研究进行彻底改变，并可能为开发用于其他滥用药物的蒸气自我管理动物模型（例如大麻，可卡因，尼古丁，甲基苯丙胺或甲苯）为基础。此外，拟议的一组研究有可能在自愿诱导酒精依赖性期间特别招募的神经元靶标，这对于开发新型治疗方法可能有用。