Withdrawal-Stress, Anxiety, and Amygdala Neurophysiology

戒断压力、焦虑和杏仁核神经生理学

• 批准号: 8606725
• 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 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606725
• 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; behavior measurement; 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; 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（由申请人提供）：慢性乙醇暴露后的戒断压力导致焦虑样行为增加，这有助于戒酒的复发。但是，关于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，我们已经表明，横向/基底外侧杏仁核（BLA）中的大鼠谷氨酸能和GABA能突触功能受到慢性乙醇暴露和戒断的巨大调节。同样，大鼠BLA CRF/尿果素系统似乎增强了兴奋性BLA反应。谷氨酸，GABA和CRF/尿道素的慢性乙醇相关的改变都可能导致戒断焦虑。但是，任何个人改变的确切贡献都与它们在乙醇中的动物中的基本贡献相混淆。 C57BL/6J（B6）和DBA/2J（D2）鼠标提供了另一种方法。这些近交系在许多不同的乙醇相关行为（包括它们对慢性乙醇暴露和戒断的行为敏感性）方面差异很大。通过在当前应用中提供的初步证据显示出更高的D2敏感性，这将扩展到戒断焦虑。此外，我们发表的和初步的发现表明，这两种小鼠系中的BLA GABA能和潜在的谷氨酸能突触功能明显不同。这强烈表明，慢性乙醇暴露在一种菌株中产生大量戒断，而不是另一种菌株，可用于突出单个神经生理学变化，并具有最大的行为影响。因此，提出的实验将检验中心假设，即D2小鼠焦虑的较大焦虑增加将通过BLA兴奋性神经递质系统（如谷氨酸和CRF/尿果素）的更大增加而反映出。我们对这些系统以及GABA能量功能的主要电生理分析将与B6，D2和转基因小鼠的戒断压力期间的焦虑量融为一体。拟议的实验之所以重要，是因为它们提供了一个独特的机会来为未来疗法定义特定的BLA神经生物学靶标。