Neurosteroids and alcohol self-administration and reinstatement

神经类固醇和酒精的自我给药和恢复

• 批准号: 8467577
• 负责人: Marcia J Ramaker
• 金额: $ 3.86万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8467577
• 关键词: Affect; Affinity; Agonist; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Allopregnanolone; American; Animal Model; Area; Behavior; Bicuculline; Brain; Conditioned Stimulus; Cues; Data; Disease; Dose; Drug Exposure; Ethanol; Exhibits; Extinction (Psychology); Family; Goals; Health; Individual; Injection of therapeutic agent; Lead; Light; Literature; Measures; Mediating; Microinjections; Mus; National Institute on Alcohol Abuse and Alcoholism; Nucleus Accumbens; Oral; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Production; Property; Receptor Activation; Regulation; Relapse; Resistance; Rodent; Role; Self Administration; Site; Societies; Stimulus; Sucrose; Synapses; Testing; Training; alcohol effect; alcohol exposure; alcohol reinforcement; alcohol relapse; alcohol seeking behavior; alcohol use disorder; analog; base; follow-up; gamma-Aminobutyric Acid; ganaxolone; insight; knock-down; male; neurosteroids; novel; novel therapeutics; psychologic; receptor; response

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.

描述(由申请人提供)：目前酒精使用障碍的治疗选择导致大多数患者的依从性低和复发率高。为了开发新的治疗方案，需要加强对调解酒精滥用的替代途径的了解。这个项目的目标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场所，以及突触外GABAA受体如何影响酒精强化。这项研究的目的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接受自我给药训练的小鼠身上进行测试。此外，突触外GABAA受体激动剂的作用将检验NAC中这一亚类受体在饮酒中的作用。目的2将测量全身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。将测量一种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，还将测试突触外GABAA受体的参与程度，以揭示这一亚类受体是否参与酒精恢复。以前与酒精配对的刺激，以及接触酒精，可能是戒毒者寻求酒精和复发的有力触发因素。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检测，以提供对复发潜在机制的新见解。这一提议将检验神经类固醇水平和突触外GABAA受体激活是酒精摄取和寻求的重要决定因素的假设，并且这种影响在一定程度上是由NAC介导的。