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: 8202526
• 负责人: Marcia J Ramaker
• 金额: $ 4.18万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8202526
• 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. 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.

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。为了开发新的治疗选择，需要加强对介导酒精滥用的替代途径的理解。该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位点，以及突触外GABAA受体如何影响酒精强化。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。将使用在操作性自我给药范例中训练的小鼠来测试丘脑核中神经类固醇水平对饮酒的影响。此外，突触外GABAA受体激动剂的作用将检查NAc中该受体亚类对饮酒的作用。目的2将测量全身神经类固醇水平和突触外GABAA受体激活影响乙醇恢复的程度。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，以揭示该受体亚类是否参与酒精复吸。先前与酒精配对的刺激，以及暴露于酒精，可能是解毒用户寻求酒精和复发的有力触发因素。因此，还将检查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作用，以提供对复发潜在机制的新见解。这项建议将测试的假设，神经类固醇水平和突触外GABAA受体激活的重要决定因素的乙醇摄入量和寻求，这种影响是部分介导的NAC。 公共卫生相关性：酒精使用障碍可能是社会的危险和昂贵的负担。该项目的长期目标是加强对介导酒精滥用的神经类固醇通路和受体定位的理解，以揭示新的治疗选择。