GABAergic mechanisms of adolescent and emerging adult vulnerability to alcohol

青少年和新兴成人易受酒精影响的 GABA 机制

• 批准号: 9235212
• 负责人: Scott D. Moore
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9235212
• 关键词: Acute; Adolescence; Adolescent; Adult; Age; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Amygdaloid structure; Anxiety; Behavior; Behavioral; Brain; Brain region; Chronic; Cognition; Development; Dose; Electrophysiology (science); Ethanol; Family; General Population; Health; Heavy Drinking; High Prevalence; Hippocampus (Brain); Lead; Learning; Link; Long-Term Effects; Measures; Mediating; Medical; Memory; Military Personnel; Neurologic; Neurologic Effect; Neurons; Pattern; Pharmaceutical Preparations; Pharmacology; Physiological; Play; Population; Prevalence; Prevention strategy; Protein Isoforms; Proteomics; Publishing; Rattus; Risk; Role; Self Administration; Sleep; Slice; Testing; Time; Veterans; adolescent alcohol exposure; age group; aged; alcohol abuse therapy; alcohol consequences; alcohol effect; alcohol exposure; alcohol response; alcohol sensitivity; alcoholism therapy; binge drinking; cell type; dentate gyrus; drinking; emerging adult; emerging adulthood; excitatory neuron; gamma-Aminobutyric Acid; heavy drinking during adolescence; in vivo; inhibitory neuron; insight; morris water maze; peer; problem drinker; public health relevance; receptor; social; underage drinking

DESCRIPTION (provided by applicant): Veterans and their families are disproportionately burdened by the medical and social consequences of alcohol abuse because the prevalence of alcoholism in veterans is over 3 times that of the general population. While the cause of increased alcohol abuse by veterans is not known, a growing body of evidence suggests a link between brain changes caused by alcohol drinking during adolescence or emerging adulthood and the later development of alcohol abuse in adults. Heavy drinking during adolescence / emerging adulthood may disrupt the maturation of vulnerable brain circuits and produce long-term changes in cognition, behavior, and sensitivity to ethanol. Because military personnel ages 18-25 use alcohol more frequently and at higher doses than civilians, veterans are more likely to have engaged in heavy drinking at a time when the brain may be particularly sensitive to the long-lasting consequences of ethanol exposure. Recent advances in the alcohol field are producing insights into the neurological mechanisms that underlie the unique ethanol sensitivity of the adolescent and emerging adult brain. In particular, extrasynaptic GABAA receptors (eGABAARs) have been identified as important ethanol targets. These developmentally regulated GABAARs control the excitability of neurons and brain circuits and modulate anxiety, learning, sleep, and ethanol drinking. Recent evidence suggests that 2 extrasynaptic GABAAR subtypes, �4�� and �5�?, regulate neuron excitability and ethanol sensitivity in the hippocampus and amygdala. Recently published studies have shown that binge-pattern ethanol exposure during adolescence produces long-term changes in the ethanol sensitivity of eGABAAR-mediated tonic inhibition, and these changes may involve �4�� and �5�? GABAARs. Two mechanisms control the ethanol sensitivity of eGABAAR-mediated tonic inhibition: the GABAAR subtype expressed and the ambient GABA concentration. Critical interactions between these mechanisms may underlie developmental changes in the ethanol sensitivity of neurons and brain circuits during adolescence and emerging adulthood. The aims of this project will (1) use targeted proteomics and electrophysiology in ex vivo brain slices to thoroughly characterize the roles of eGABAAR subtype expression and ambient GABA in controlling tonic inhibition in the dentate gyrus and amygdala; (2) antagonize the effects of ethanol on �4�� GABAARs to determine if they play an essential role in producing the long-term effects of binge-pattern ethanol exposure; and (3) pharmacologically manipulate eGABAARs in vivo to demonstrate a critical link between changes in eGABAAR-mediated tonic inhibition and ethanol-induced changes in cognition and ethanol self- administration. Drugs that regulate eGABAARs are currently available, and more are in development; therefore, these studies of tonic inhibition's role in producing ethanol's neurological effects may have near-term translational value. The results of these studies could lead to the identification of new treatments for alcohol abuse.

描述（由申请人提供）： 退伍军人及其家庭因酗酒的医疗和社会后果而承受不成比例的负担，因为退伍军人酗酒的流行率是普通人群的3倍多。虽然退伍军人酗酒增加的原因尚不清楚，但越来越多的证据表明，青春期或成年初期饮酒引起的大脑变化与成年人酗酒的后期发展之间存在联系。在青春期/成年初期大量饮酒可能会破坏脆弱的大脑回路的成熟，并在认知，行为和对乙醇的敏感性方面产生长期变化。由于18-25岁的军人比平民更频繁地使用酒精，而且剂量更高，退伍军人更有可能在大脑对乙醇暴露的长期后果特别敏感的时候大量饮酒。 酒精领域的最新进展正在深入了解青少年和新兴成人大脑独特的乙醇敏感性背后的神经机制。特别是，突触外GABAA受体（eGABAAR）已被确定为重要的乙醇靶点。这些发育调节的GABAAR控制神经元和大脑回路的兴奋性，并调节焦虑，学习，睡眠和酒精饮用。最近的证据表明，2个突触外GABAAR亚型，4和5，调节海马和杏仁核中的神经元兴奋性和乙醇敏感性。最近发表的研究表明，青少年时期的酗酒模式乙醇暴露会导致eGABAAR介导的紧张性抑制的乙醇敏感性发生长期变化，这些变化可能涉及4和5？ GABAAR。 两种机制控制eGABAAR介导的紧张性抑制的乙醇敏感性：表达的GABAAR亚型和环境GABA浓度。这些机制之间的关键相互作用可能是青春期和成年期神经元和脑回路乙醇敏感性的发展变化的基础。本项目的目标是：（1）利用离体脑片的靶向蛋白质组学和电生理学，全面表征eGABAAR亚型表达和环境GABA在控制齿状回和杏仁核紧张性抑制中的作用;（2）拮抗乙醇对4 β-GABAAR的影响，以确定它们是否在产生酒精暴露的长期效应中起重要作用;和（3）在体内连续操作eGABAAR以证明eGABAAR介导的紧张性抑制的变化与乙醇诱导的认知变化和乙醇自身给药之间的关键联系。 调节eGABAAR的药物目前可用，并且更多的药物正在开发中;因此，这些关于强直抑制在产生乙醇神经效应中的作用的研究可能具有近期的转化价值。这些研究的结果可能会导致确定新的治疗酒精滥用的方法。