Withdrawal-Stress, Anxiety, and Amygdala Neurophysiology

描述（由申请人提供）：慢性乙醇暴露后的戒断应激导致焦虑样行为增加，导致戒酒者复发。然而，我们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，大鼠杏仁核外侧/基底外侧（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。类似地，大鼠BLA CRF/urocortin系统似乎增强兴奋性BLA反应。慢性乙醇相关的谷氨酸、GABA和CRF/urocortin改变都可能导致戒断焦虑。但是，任何个体改变的精确贡献都被它们在乙醇实验动物中的基本贡献所混淆。C57 BL/6 J（B6）和DBA/2 J（D2）小鼠提供了另一种方法。这些近交系在许多不同的乙醇相关行为方面存在显着差异，包括它们对慢性乙醇暴露和戒断的行为敏感性。通过本申请中提供的初步证据，这被扩展到戒断焦虑，其显示出更大的D2敏感性。此外，我们发表的和初步的研究结果表明，BLA GABA能和潜在的谷氨酸能突触功能在这两个小鼠系是显着不同的。这有力地表明，慢性乙醇暴露产生大量的戒断焦虑，而不是其他菌株可以用来突出个人的神经生理学变化，最大的行为影响。因此，拟议的实验将检验中心假设，即D2小鼠中更大的戒断相关焦虑增加将反映为BLA兴奋性神经递质系统（如谷氨酸和CRF/尿皮质素）的更显著增加。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。拟议的实验是重要的，因为它们提供了一个独特的机会，以确定特定的BLA神经生物学目标，为未来的治疗。

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.