Withdrawal-Stress, Anxiety, and Amygdala Neurophysiology

戒断压力、焦虑和杏仁核神经生理学

• 批准号: 8790931
• 负责人: BRIAN A MCCOOL
• 金额: $ 18.15万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-10 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8790931
• 关键词: Address; Alcohol withdrawal syndrome; Alcohols; Amygdaloid structure; Animal Model; Animals; Anxiety; Back; Behavior; Behavioral; Biological Assay; Brain region; Cells; Characteristics; Chronic; Data; Dependence; Electrophysiology (science); Equilibrium; Ethanol; Exhibits; Exposure to; Fright; Future; Glutamates; Goals; Human; In Vitro; Inbred Mouse; Inbred Strains Mice; Inbreeding; Individual; Lateral; Literature; Measures; Modeling; Molecular; Mus; Neurobiology; Neurons; Neuropeptides; Neurotransmitters; Outcome; Pathway interactions; Phenotype; Physical Dependence; Play; Preparation; Publishing; Rattus; Relapse; Relative (related person); Research; Resistance; Resources; Rodent; Rodent Model; Role; Stress; Synapses; System; Systems Analysis; Testing; Time; Withdrawal; alcohol behavior; alcohol exposure; anxiety-like behavior; behavior measurement; behavioral outcome; behavioral pharmacology; brain tissue; cellular targeting; feeding; gamma-Aminobutyric Acid; innovation; insight; neurobiological mechanism; neurophysiology; neurotransmission; nonhuman primate; patch clamp; problem drinker; relating to nervous system; research study; response; stress reactivity; synaptic function; therapeutic target; urocortin; vapor

DESCRIPTION (provided by applicant): Withdrawal stress following chronic ethanol exposure results in heightened anxiety-like behaviors that contribute to relapse in abstinent alcoholics. However, very little is known about the neurobiological mechanisms controlling these outcomes. Animal models can make significant contributions towards understanding these issues. For example, we have shown that the rat glutamatergic and GABAergic synaptic function in the lateral/basolateral amygdala (BLA) are dramatically regulated by chronic ethanol exposure and withdrawal. Similarly, the rat BLA CRF/urocortin system appears to enhance excitatory BLA responses. Chronic ethanol-related alterations in glutamate, GABA, and CRF/urocortin all potentially contribute to withdrawal-anxiety. But, the precise contributions of any individual alteration are confounded by their fundamental contributions in ethanol-naive animals. The C57BL/6J (B6) and DBA/2J (D2) mouse offer an alternative approach. These inbred lines differ dramatically with respect to a number of different ethanol related behaviors, including their behavioral sensitivity to chronic ethanol exposure and withdrawal. This is extended to withdrawal-anxiety by preliminary evidence provided in the current application that shows greater D2 sensitivity. Furthermore, our published and preliminary findings suggest that BLA GABAergic and potentially glutamatergic synaptic function in these two mouse lines are markedly distinct. This strongly suggests that chronic ethanol exposures producing substantial withdrawal-anxiety in one strain but not the other can be used to highlight individual neurophysiological changes with the greatest behavioral impact. The proposed experiments will therefore test the central hypothesis that the greater withdrawal-related increases in anxiety in D2 mice will be reflected by more significant increases in BLA excitatory neurotransmitter systems, like glutamate and CRF/urocortin. Our primarily electrophysiological analysis of these systems as well as GABAergic function will be integrated with both behavioral measures of anxiety during withdrawal-stress in B6, D2, and genetically modified mice. The proposed experiments are significant because they offer a unique opportunity to define specific BLA neurobiological targets for future therapies.

描述(申请人提供)：慢性酒精暴露后的戒断压力会导致类似焦虑的行为加剧，从而导致戒酒者的复发。然而，对控制这些结果的神经生物学机制知之甚少。动物模型可以为理解这些问题做出重大贡献。例如，我们已经证明，慢性酒精暴露和戒断对大鼠杏仁外侧核(BLA)的谷氨酸和GABA能突触功能有显著的调节作用。类似地，大鼠BLA CRF/urocortin系统似乎增强了兴奋性BLA反应。慢性乙醇相关的谷氨酸、GABA和CRF/urocortin的改变都可能导致戒断焦虑。但是，任何个体改变的确切贡献都被它们在未接触酒精的动物身上的基本贡献所混淆。C57BL/6J(B6)和DBA/2J(D2)小鼠提供了一种替代方法。这些近交系在许多不同的酒精相关行为方面存在显著差异，包括它们对长期酒精暴露和戒断的行为敏感性。目前的申请中提供的初步证据表明，D2敏感性更高，这一点扩展到了戒断焦虑。此外，我们已发表的和初步的发现表明，这两个小鼠系的BLA-GABA能和潜在的谷氨酸能突触功能明显不同。这有力地表明，慢性酒精暴露在一种品系中产生实质性的戒断焦虑，而不是另一种品系，可以用来突出具有最大行为影响的个体神经生理变化。因此，拟议的实验将检验中心假设，即D2小鼠与戒断相关的焦虑增加将通过血乳酸兴奋性神经递质系统(如谷氨酸和CRF/urocortin)更显著的增加来反映。我们对这些系统的主要电生理分析以及GABA能功能将与B6、D2和转基因小鼠在戒断应激期间焦虑的行为测量相结合。拟议的实验具有重要意义，因为它们为未来的治疗提供了一个独特的机会来定义特定的BLA神经生物学目标。