Alcohol Vapor Self-Administration in Rats

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的动物模型，这在很大程度上阻碍了发现自愿中毒到依赖点的神经生物学机制。虽然大鼠很容易自我摄入酒精，但酒精摄入量非常低（通常为10- 90mg %，每天少于1小时），因此不会产生与酒精中毒相关的临床血液酒精水平（每天100- 200mg %，每天数小时）。已经开发了其他范式来产生大鼠的酒精依赖，但这些模型要么是被迫的，要么是被动的暴露于高剂量的酒精中，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。我们最近发明了一种新的装置，可以让老鼠自我吸收酒精蒸气。我们获得的证据表明，近亲繁殖的大鼠每天会自我施用酒精蒸气12小时以上，直至达到血液酒精含量在100- 200mg %范围内。我们建议在大鼠中使用酒精蒸气自我给药来表征和开发一种新的酒精依赖自愿诱导和维持的动物模型，并使用脑制图技术来识别介导自愿（与强迫）诱导和维持酒精依赖的神经元网络。我们最近证明，在酗酒戒断过程中，前额皮质神经元会产生GABA和促肾上腺皮质激素释放因子（CRF），但这些神经元在自愿诱导酒精依赖中的作用尚不清楚。目前的应用将直接验证前额叶皮层的GABA和CRF神经元在自愿（与强迫）诱导和维持酒精依赖过程中被募集的假设。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，提出的一系列研究有可能揭示在自愿（或被动）诱导酒精依赖过程中特异性招募的神经元靶点，这可能对开发新的治疗方法有用。

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.