Alcohol Vapor Self-Administration in Rats

描述(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的动物模型，这在很大程度上阻碍了对自愿醉酒至依赖点的神经生物学机制的发现。虽然大鼠很容易自我给予酒精，但饮酒量非常低(通常是每天10-90 mg%，每天少于1小时)，因此不会产生与酒精中毒临床相关的血液酒精水平(100-200 mg%，每天几个小时)。已经开发了其他范例来产生大鼠的酒精依赖，但这些模型使用强迫或被动暴露于高剂量酒精，从而阻碍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这个问题。我们最近开发了一种新的设备，允许大鼠自我管理酒精蒸气。我们获得的证据表明，杂交后的大鼠每天自我给予酒精蒸气12+h，直到血液中酒精含量达到100-200 mg%范围。我们建议利用酒精蒸气自我给药来描述和发展一种新的酒精依赖诱导和维持的动物模型，并使用脑电地形图技术来识别调节自愿(与强迫)诱导和维持酒精依赖的神经网络。我们最近证明，在酗酒戒断过程中，前额叶皮质产生GABA和促肾上腺皮质激素释放因子(CRF)的神经元被招募，但这些神经元在自愿诱导酒精依赖中的作用尚不清楚。目前的应用将直接测试这一假设，即在自愿(与强制)诱导和维持酒精依赖期间，前额叶皮质中的GABA和CRF神经元被招募。这些研究的结果有可能从根本上改变酒精中毒的临床前研究，并可能为开发其他滥用药物，如大麻、可卡因、尼古丁、甲基苯丙胺或甲苯的蒸汽自我给药动物模型奠定基础。此外，拟议的一系列研究有可能揭示在自愿(v.被动)酒精依赖诱导过程中专门招募的神经元靶点，这可能有助于开发新的治疗方法。

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.