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，这极大地阻碍了发现自愿中毒到依赖程度的神经生物学机制。虽然大鼠很容易自我给药酒精，但消耗的酒精量非常低（通常为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（每天数小时为100-200 mg%）。已经开发了其他范例来产生酒精依赖的大鼠，但这些模型使用强迫或被动暴露于高剂量的酒精，从而防止调查的神经生物学机制，自愿诱导和酒精依赖的维持。本申请直接解决了这个问题。我们最近开发了一种新的装置，可以让老鼠自我管理酒精蒸汽。我们获得的证据表明，远系繁殖的大鼠将每天自我给予酒精蒸汽12+ h，达到血液酒精水平在100-200 mg%范围内。我们建议表征和开发一种新的动物模型的自愿诱导和酒精依赖的维持使用酒精蒸汽自我管理的大鼠和使用脑映射技术，以确定介导的自愿（与强迫）诱导和维持酒精依赖的神经网络。我们最近证明，前额叶皮层神经元产生GABA和促肾上腺皮质激素释放因子（CRF）的酒精狂欢饮酒戒断过程中招募，但这些神经元在自愿诱导酒精依赖的作用是未知的。目前的应用将直接测试的假设，GABA和CRF神经元在前额叶皮层招募自愿（与强迫）诱导和酒精依赖的维持。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）的蒸汽自我管理动物模型奠定基础。此外，拟议的一组研究有可能揭示在自愿（v.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.