Withdrawal-Stress, Anxiety, and Amygdala Neurophysiology

描述（由申请人提供）：慢性酒精暴露后的戒断压力导致焦虑样行为加剧，有助于戒断性酗酒者复发。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，我们已经表明，大鼠外侧/基底外侧杏仁核（BLA）的谷氨酸能和gaba能突触功能受到慢性乙醇暴露和戒断的显著调节。同样，大鼠BLA CRF/尿皮质素系统似乎增强了兴奋性BLA反应。慢性酒精相关的谷氨酸、GABA和CRF/尿皮质素的改变都可能导致戒断性焦虑。但是，任何个体变化的精确贡献都与它们在未接触乙醇的动物中的基本贡献相混淆。C57BL/6J （B6）和DBA/2J （D2）小鼠提供了另一种方法。这些自交系在许多不同的乙醇相关行为方面差异很大，包括它们对慢性乙醇暴露和戒断的行为敏感性。在当前应用中提供的初步证据表明，D2敏感性更高，这扩展到戒断焦虑。此外，我们发表的和初步的研究结果表明，这两种小鼠系的BLA - gaba能突触功能和潜在的谷氨酸能突触功能明显不同。这强烈表明，慢性乙醇暴露在一个品系中产生大量的戒断焦虑，而在另一个品系中则没有，这可以用来强调具有最大行为影响的个体神经生理变化。因此，拟议的实验将验证一个中心假设，即D2小鼠中与戒断相关的焦虑程度的增加将反映在BLA兴奋性神经递质系统（如谷氨酸和CRF/尿皮质素）的显著增加上。我们对这些系统以及gaba能功能的主要电生理分析将与B6、D2和转基因小鼠在戒断应激期间的焦虑行为测量相结合。提出的实验意义重大，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神经生物学靶点。

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. PUBLIC HEALTH RELEVANCE: The proposed research will help establish the neural systems important for abnormal behaviors caused by chronic ethanol exposure. The application uses rodent models, specifically inbred mouse strains, behavioral measures of anxiety, and a number of characterizations in brain tissue to accomplish this overall goal.