Genetic Regulation of the Ethanol/Anxiety Interaction: Neurobiological Mechanisms

描述(由申请人提供)：压力-酒精的相互作用显然会导致酒精滥用的后果，包括在戒除慢性接触期间增加的焦虑。然而，人们对这些复杂关系的生物学基础知之甚少。动物模型可能会对我们理解这些问题做出重大贡献。例如，对遗传定义的近交系小鼠品系进行比较，将提供一个独特的机会，来理解调节对慢性酒精和戒断的适应的相关遗传机制。同样，将这些菌株置于明确的环境应激源之下，将有助于我们对影响与酒精接触相关的行为后果(如焦虑)的“经验依赖”机制有重要的了解。虽然已知有许多大脑区域控制恐惧/焦虑行为，但杏仁外侧核/基底外侧杏仁核是“焦虑”回路的中心组成部分。因为杏仁GABAA受体调节焦虑行为，这个系统中依赖酒精和压力的适应可能对与它们相互作用相关的行为后果很重要。我们的初步结果表明，C57BL/6(B6)和DBA/2J(D2)近交系小鼠在基础焦虑以及杏仁外侧核(BLA)表达的GABAA受体的功能和分子表达上存在显著差异。初步研究结果还表明，慢性酒精暴露会不同地改变B6和D2神经元表达的BLA GABAA受体的功能。因此，这一应用将专门测试中央假设，即外侧/基底外侧杏仁核GABAA受体的表达/功能是BLA GABAA的表型标志，BLA GABAA是应激-酒精相互作用的相对焦虑相关易感性。我们将使用住房操作和慢性酒精吸入来验证我们的中心假设，以调查环境应激源、杏仁核GABA能表达/功能和戒断的神经生物学后果之间的相互作用。我们将具体整合行为学、分子生物学和电生理学的实验方法，以更好地理解与焦虑样行为相关的应激-酒精相互作用。最终，我们希望我们的方法将使我们最终能够表征与这些关系相关的调节分子和神经生理适应的特定遗传机制。

DESCRIPTION (provided by applicant): Stress-alcohol interactions clearly contribute to consequences of alcohol abuse, including increased anxiety during withdrawal from chronic exposure. However, little is known about the biological basis for these complex relationships. Animal models are likely to make significant contributions to our understanding of these issues. For example, comparisons between genetically-defined inbred mouse strains would provide a unique opportunity to understand the relevant genetic mechanisms regulating adaptations to chronic ethanol and withdrawal. Likewise, subjecting these strains to defined environmental stressors would yield important insight into the 'experience-dependent' mechanisms that influence the behavioral consequences (e.g. anxiety) related to this alcohol exposure. Although numerous brain regions are known to govern fear/anxiety behaviors, the lateral/basolateral amygdala is a central component of 'anxiety' circuitry. Because amygdale GABAA receptors regulate anxiety behavior, ethanol- and stress-dependent adaptations in this system may be important for the behavioral consequences related to their interactions. Our preliminary results suggest that the C57BL/6 (B6) and DBA/2J (D2) inbred mouse lines differ markedly in their basal anxiety as well as the functional and molecular expression of GABAA receptors expressed in lateral/basolateral amygdale (BLA). Preliminary findings also indicate that chronic ethanol exposure differentially alters the function of BLA GABAA receptors expressed by B6 and D2 neurons. Therefore, this application will specifically test the central hypothesis that lateral/basolateral amygdala GABAA receptor expression/function is a phenotypic marker for BLA GABAA the relative anxiety-related liability of stress-alcohol interactions. We will test our central hypothesis using housing manipulations and chronic ethanol inhalation to investigate the interactions between environmental stressors, amygdala GABAergic expression/function, and the neurobiological consequences of withdrawal. We will specifically integrate behavioral, molecular biological, and electrophysiological experimental approaches to better understand the stress-ethanol interactions related to anxiety-like behaviors. Ultimately, we hope our approach will allow us to eventually characterize the specific genetic mechanisms regulating the molecular and neurophysiological adaptations associated with these relationships.