Altered Accumbens Signaling Following Ethanol Exposure

乙醇暴露后伏隔信号传导发生改变

• 批准号: 7454214
• 负责人: Frederic Woodward Hopf
• 金额: $ 31.28万
• 依托单位: ERNEST GALLO CLINIC AND RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7454214
• 关键词: Abstinence; Action Potentials; Address; Adult; Agonist; Alcohols; Animals; Apamin; Appendix; Behavior; Biological Assay; Brain; Calcium; Calcium Channel; Cells; Chronic; Cocaine; Condition; Consumption; Coupled; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Dependency; Development; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Dose; Electrophysiology (science); Ethanol; Exposure to; Fire - disasters; Forskolin; Goals; Human; Image; Ion Channel; Medial; Mediating; Methods; Motivation; Neurons; Neurophysiology - biologic function; Nomifensine; Nucleus Accumbens; Numbers; Pharmaceutical Preparations; Physiologic pulse; Play; Potassium; Potassium Channel; Predisposition; Property; Proteins; Pulse taking; Rattus; Receptor Signaling; Regulation; Relapse; Relative (related person); Research Personnel; Role; Self Administration; Self-Administered; Signal Transduction; Slice; Source; Stimulus; Sucrose; System; Time; Training; Week; Western Blotting; Wistar Rats; addiction; alcohol craving; alcohol exposure; behavior influence; craving; day; deprivation; dopamine transporter; drug of abuse; inhibitor/antagonist; mature animal; motivated behavior; patch clamp; problem drinker; programs; receptor; receptor function; research study; uptake; voltage clamp; weanling animal

DESCRIPTION (provided by applicant): Human alcoholics attempting to maintain abstinence often undergo major periods of craving, relapse and continued consumption. To address these problems, it is important to identify alterations in neural function that persist after ethanol exposure has ceased, as these changes are likely to enhance susceptibility to relapse-inducing stimuli. Functional changes within the nucleus accumbens (NAcb) could potently alter nduction of relapse, as the NAcb is implicated in responsiveness to many conditioned stimuli, as well as consumption of and reinstatement for drugs of abuse, and several human imaging studies suggest a role for the NAcb in cravings in alcoholics and cocaine addicts. The major goal of this proposal is to determine whether basic spike firing and dopaminergic modulation of firing in the NAcb are persistently altered during abstinence following repeated ethanol exposure. We focus on spike firing, as it is the predominant mechanism by which neurons transmit information. Spike firing will be analyzed using patchclamp electrophysiology in NAcb brain slices from adult animals that operantly self-administered ethanol for 40-45 days, then underwent 3 weeks of abstinence. Animals self-administering sucrose then undergoing abstinence will act as a control. Our preliminary data provide the first evidence that spike firing in NAcb core neurons is enhanced during abstinence following repeated ethanol exposure, which may be due to inhibition of a calcium-dependent potassium current (I[SKICa2+]). Specific aim 1 will examine whether basic spike firing properties in the NAcb are altered after 3 and 6 months of abstinence following ethanol self-administration. Specific aim 2 will use voltage-clamp methods and specific antagonists to characterize the calcium sources that contribute to I[SKCa2+[ activation, and which might be reduced in ethanol-trained animals during abstinence. Specific aim 3 will investigate whether modulation of spike firing by dopamine is altered following repeated ethanol exposure, as dopamine signaling within the NAcb regulates reinstatement for several drugs of abuse, and NAcb dopamine can contribute strongly during ethanol self-administration. Altered spike firing and dopamine signaling in the NAcb could significantly influence the behavioral contribution of the NAcb, and in this way facilitate the onset of relapse.

描述（由申请人提供）：试图保持禁欲的人类酗酒者通常会经历渴望，复发和持续消费的主要时期。为了解决这些问题，重要的是要确定乙醇暴露停止后持续存在的神经功能的改变，因为这些变化可能会增强对复发诱导刺激的敏感性。神经核（NAcb）内的功能变化可能会有效地改变复发的诱导，因为NAcb涉及对许多条件刺激的反应，以及滥用药物的消耗和恢复，并且一些人类成像研究表明NAcb在酗酒者和可卡因成瘾者的渴望中发挥作用。这项建议的主要目标是确定是否在NAcb的基本尖峰放电和多巴胺能调制放电持续改变在禁欲重复乙醇暴露。我们专注于尖峰放电，因为它是神经元传递信息的主要机制。将使用膜片钳电生理学在来自成年动物的NAcb脑切片中分析尖峰放电，所述成年动物操作性地自我施用乙醇40-45天，然后经历3周的禁欲。动物自我给药蔗糖，然后进行禁欲将作为对照。我们的初步数据提供了第一个证据表明，在NAcb核心神经元的尖峰放电增强在禁欲重复乙醇暴露后，这可能是由于抑制钙依赖性钾电流（I[SKICa 2 +]）。具体目标1将检查乙醇自我给药后禁欲3个月和6个月后NAcb中的基本尖峰放电特性是否改变。具体目标2将使用电压钳方法和特定拮抗剂来表征有助于I[SKCa 2 +]激活的钙源，并且在戒酒期间接受乙醇训练的动物中可能会减少。具体目标3将研究多巴胺对尖峰放电的调制是否在重复乙醇暴露后改变，因为NAcb内的多巴胺信号传导调节几种滥用药物的恢复，并且NAcb多巴胺可以在乙醇自我给药期间做出强烈贡献。NAcb中改变的尖峰放电和多巴胺信号传导可以显著影响NAcb的行为贡献，并且以这种方式促进复发的发生。