Neurosteroids and alcohol self-administration and reinstatement

描述（由申请人提供）：目前酒精使用障碍的治疗方案导致大多数患者的低依从性和高复发率。为了开发新的治疗方案，需要加强对介导酒精滥用的替代途径的理解。该项目的目的是更好地了解神经类固醇产生影响酒精摄入的机制和作用位点，以及突触外GABAA受体如何影响乙醇强化。本研究的目的1将测量NAc神经类固醇水平和突触外GABAA受体激活改变乙醇自我给药的程度。伏隔核中神经类固醇水平对饮酒的影响将在操作性自我给药范式中使用训练的小鼠进行测试。此外，一种突触外GABAA受体激动剂的作用将检验这类受体在NAc中对饮酒的作用。目的2将测量系统神经类固醇水平和突触外GABAA受体激活对乙醇恢复的影响程度。将测量合成神经类固醇对恢复行为的剂量反应曲线，以检查神经类固醇水平对酒精寻求的影响。此外，将测试突触外GABAA受体的参与，以揭示这类受体是否参与酒精恢复。先前与酒精搭配的刺激，以及接触酒精，都可能是寻求酒精和戒毒者复发的有力诱因。因此，神经类固醇激动剂或突触外GABAA受体激动剂对口服乙醇或线索诱导的恢复的影响也将被研究，以提供对复发机制的新见解。这一建议将验证神经类固醇水平和突触外GABAA受体激活是乙醇摄入和寻找的重要决定因素的假设，并且这种影响部分由NAc介导。

DESCRIPTION (provided by applicant): Current treatment options for alcohol use disorders result in low compliance and high relapse rates for most patients. In order to develop novel therapeutic options, enhanced understanding of alternative pathways that mediate alcohol abuse is needed. The goal of this project is to better understand the mechanism and locus of action by which neurosteroid production affects alcohol intake, and how extrasynaptic GABAA receptors influence ethanol reinforcement. Aim 1 of this study will measure the extent to which NAc neurosteroid levels and extrasynaptic GABAA receptor activation alter ethanol self-administration. The influence of neurosteroid levels in the nucleus accumbens on alcohol drinking will be tested using mice trained in an operant self-administration paradigm. In addition, the effects of an extrasynaptic GABAA receptor agonist will examine the role of this subclass of receptors in the NAc on alcohol drinking. Aim 2 will measure the extent to which systemic neurosteroid levels and extrasynaptic GABAA receptor activation affect ethanol reinstatement. The dose response curve of a synthetic neurosteroid on reinstatement behavior will be measured to examine the influence of neurosteroid levels on alcohol seeking. Further, the involvement of extrasynaptic GABAA receptors will be tested to reveal whether this subclass of receptors is involved in alcohol reinstatement. Stimuli previously paired with alcohol, as well as exposure to alcohol, can be a potent trigger of alcohol-seeking and relapse in detoxifying users. Therefore, the effect of the neurosteroid agonist or extrasynaptic GABAA receptor agonist on oral ethanol or cue-induced reinstatement will also be examined to provide novel insight into mechanisms underlying relapse. This proposal will test the hypothesis that neurosteroid levels and extrasynaptic GABAA receptor activation are important determinants of ethanol intake and seeking, and that this effect is in part mediated by the NAc. PUBLIC HEALTH RELEVANCE: Alcohol use disorders can be a dangerous and expensive burden on society. The long-term goal of this project is to enhance understanding of neurosteroid pathways and receptor localizations that mediate alcohol abuse, in order to shed light on novel therapeutic options.