Alcohol Vapor Self-Administration in Rats

点击翻译按钮获取中文摘要

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.