GABAA R-subunit changes in adolescents by a cytokine/ethanol withdrawal protocol

细胞因子/乙醇戒断方案导致青少年 GABAA R 亚基发生变化

• 批准号: 8114192
• 负责人: GEORGE R BREESE
• 金额: $ 33.45万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-10 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8114192
• 关键词: Address; Adolescence; Adolescent; Adult; Age; Alcohol abuse; Alcohol withdrawal syndrome; Alcoholism; Amygdaloid structure; Anxiety; Behavior; Brain; Brain region; CCL2 gene; Characteristics; Chronic; Data; Diet; Dose; Ethanol; Exposure to; Figs - dietary; Foundations; GABA-A Receptor; Goals; Health; Hippocampus (Brain); Inflammatory; Ink; Interleukin-1; Left; Lipopolysaccharides; Measures; Membrane; Neurons; Pathology; Pattern; Pharmaceutical Preparations; Predisposition; Probability; Protocols documentation; Rattus; Relapse; Reporting; Research; Role; Site; Social isolation; Specificity; Stress; Synapses; TNF gene; Testing; Thalamic structure; Time; Withdrawal; Work; alcohol exposure; alcohol pharmacology; base; behavioral sensitization; biological adaptation to stress; cytokine; drinking; gamma-Aminobutyric Acid; prevent; problem drinker; receptor; receptor function; relating to nervous system; underage drinking

DESCRIPTION (provided by applicant): Drinking during adolescence enhances the probability of alcoholism upon reaching adulthood. Likewise, stress has been demonstrated to have an important role in sustaining alcohol abuse. In rats, repeated stresses prior to chronic ethanol sensitized withdrawal-induced anxiety. Based upon stress increasing cytokines in brain in adolescent and adult rats, preliminary research in adolescent and adult rats demonstrated that repeated weekly lipopolysaccharide (LPS) dosing to increase cytokines in brain followed by 5 days of ethanol (LPS/withdrawal protocol) sensitized withdrawal- induced anxiety and increased the 14-GABA(A) receptor subunit in brain 3 days after withdrawal. This effort supports the conclusion that cytokines contribute to the action of stress to enhance adaptive change induced by ethanol. Therefore, studies in adolescent rats will first characterize the time course of the 14 subunit change in cortex during and after the LPS/withdrawal protocol. Subsequently, it will be determine if this increase in the 14 subunit is accompanied by changes in 11, 15, 32, & 4 GABA(A) receptor subunits. To assess if this adaptive change has regional specificity, these assessments will be made in other regions of brain including the hippocampus, thalamus, and amygdala. To examine GABA(A) receptor function, electrophysiological studies will be performed to test if changes in synaptic and extrasynaptic GABA function occur for an extended period after the LPS/withdrawal protocol. Additionally, pharmacological studies will be carried out to identify selected GABA(A) receptor subunits at these cellular sites in chosen brain regions. Finally, studies will be undertaken to determine if blocking sensitization of ethanol withdrawal-induced anxiety induced by the LPS/withdrawal protocol will prevent the adaptive change in GABA(A) receptor subunits and diminish electrophysiological changes at synaptic and extrasynaptic sites. This latter strategy will be accomplished by preventing the LPS/withdrawal protocol behavioral sensitization of ethanol withdrawal-induced anxiety by administering drugs that block this sensitization when given prior to each of the weekly LPS doses injected before ethanol exposure. This work will test the hypothesis that the LPS/withdrawal protocol induction of persistent adaptation in GABA(A) receptor function and functional changes at synaptic and extrasynaptic sites in adolescent rats will correlate with the sensitization of withdrawal-induced anxiety induced by this protocol. The data collected should provide a foundation for understanding the role cytokines contribute to stress support of the functional pathology that increases adolescent susceptibility to continued alcohol abuse as adults. PUBLIC HEALTH RELEVANCE inking during adolescence enhances the probability of being an alcoholic during adulthood. Additionally, stress is an important aspect of sustaining relapse to drinking. Since cytokines contribute to stress responses, this proposal examines adaptive changes in adolescent rats that result from an interaction of cytokines and ethanol.

描述（由申请人提供）：青春期饮酒可以提高成年后酒精中毒的可能性。同样，已经证明压力在维持酗酒中起着重要作用。在大鼠中，在慢性乙醇敏感性戒断引起的焦虑之前的重复应力。基于青少年和成年大鼠大脑中的细胞因子的增加，青少年和成年大鼠的初步研究表明，每周重复的每周脂多糖（LPS）剂量以增加大脑中的细胞因子，然后在5天的乙醇（LPS/戒断方案/戒断方案）中提高降低焦虑症的焦虑症和戒断，并增加了14-gaba sups sups subnit sup subnit sup subunit in Brinait。这项努力支持这样的结论，即细胞因子有助于压力的作用增强乙醇引起的适应性变化。因此，对青少年大鼠的研究将首先表征在LPS/撤回方案期间和之后皮质的14个亚基变化的时间过程。随后，将确定14个亚基的增加是否伴随着11、15、32和4 GABA（a）受体亚基的变化。为了评估这种适应性变化是否具有区域特异性，这些评估将在包括海马，丘脑和杏仁核在内的其他大脑区域进行。为了检查GABA（A）受体功能，将进行电生理研究，以测试LPS/撤回方案后的突触和突触外GABA功能的变化。此外，将进行药理学研究，以确定所选脑区域这些细胞部位的选定GABA（A）受体亚基。最后，将进行研究，以确定阻塞LPS/戒断方案引起的乙醇戒断诱导焦虑的敏化是否将防止GABA（a）受体亚基的适应性变化并减少突触外和外突触部位的电生理变化。后一种策略将通过防止LPS/戒断方案的行为敏化乙醇戒断引起的焦虑的行为敏化，通过给药，在每周注射乙醇暴露之前注入的每周LPS剂量之前给予阻止这种敏化的药物。这项工作将检验以下假设：GABA（a）受体功能持续适应的LPS/撤回方案诱导青少年大鼠突触和突触外部位的功能变化将与该方案引起的戒断焦虑的敏感性相关。收集的数据应为了解细胞因子的作用有助于对功能病理的压力支持，从而增加对持续酗酒的成年人的敏感性的压力支持。青春期公共卫生相关性墨水提高了成年期间酗酒的可能性。此外，压力是维持饮酒复发的重要方面。由于细胞因子会导致压力反应，因此该建议研究了由细胞因子和乙醇相互作用引起的青少年大鼠的适应性变化。