Chronic alcohol affects stress-induced cytokines and cytokine neural function

描述（由申请人提供）：在戒酒期间，酗酒者的压力诱导下丘脑-垂体-肾上腺轴反应功能障碍，fMRI反应增加，伴有负面影响，复发时过量饮酒。尽管这些有据可查的事件引起的压力，酗酒者，这些促进功能障碍性反应的神经基础是未知的。在这方面，即使促肾上腺皮质激素释放因子（CRF）被认为有助于慢性酒精（CA）后的应激诱导的功能障碍，一个被忽视的领域是细胞因子的应激增加也有助于禁欲期间的这些应激作用的神经介导的可能性。本研究的目的是为以下假设提供支持：CA诱导持续的神经适应不良，其支持与功能障碍反应相关的选定脑区域中细胞因子的应激诱导，促进复发模型中的应激和尼古丁诱导的饮酒，改变可影响应激诱导的脑细胞因子表达的因素，并加强中央杏仁核（CeA）神经元的细胞因子反应，中央杏仁核是支持压力诱导的负面影响的大脑部位。将要采取的创新战略将有助于检验这一假设。研究将首先评估具有不同CA暴露的青少年和成年大鼠是否诱导脑中区域分布细胞因子的共同增加，但CA后应激诱导的细胞因子增加的持续时间不同。随后，为了进一步测试细胞因子在应激中的作用，将确定细胞因子是否将替代酒精剥夺效应（ADE）的应激促进和对酒精的操作性反应的增强。为了探索脑细胞因子的程度增加的压力单独或CA后，调查将确定是否在压力单独和/或CA暴露后的细胞因子增加的变化与CRF活性，TLR 4受体的内源性激动剂的间接参与，或HPA轴功能障碍的诱导。为了探索CA后应激释放的细胞因子的神经作用，将在对照组和CA暴露后探索神经兴奋性的变化、GABA和/或谷氨酸的突触前释放以及细胞因子引起的CeA神经元的突触后变化。一个特别创新的组成部分是表征细胞类型敏感的细胞因子的行动，在侧部或内侧部分的CeA与催产素或加压素，分别和探索细胞因子对CeA神经元的神经行为是否依赖于CRF。随着这些重要的过程，以解决有关细胞因子在大脑中的神经介导的问题，一个合理的基础，预计将出现CA暴露后的压力启动的细胞因子的行动，有助于与压力相关的负面后果，在戒酒酒精。这一创新努力对于重新定向药物发现计划至关重要，以便改善治疗与压力相关的酒精滥用的治疗方法。

DESCRIPTION (provided by applicant): During abstinence in alcoholics, stress induces a dysfunctional HPA axis response, an increased fMRI response accompanied by negative affect, and excess drinking upon relapse. In spite of these well documented events induced by stress in alcoholics, the neural basis of these facilitated dysfunctional responses is unknown. In this respect, even though corticotropin releasing factor (CRF) is accepted to contribute to stress induced dysfunctions after chronic alcohol (CA), an overlooked area is the possibility that the stress increase in cytokines also contributes to neuromediation of these effects of stress during abstinence. The goal of the present research is to provide support for the hypothesis that CA induces a persisting neural maladaptation that supports the stress induction of cytokines in selected brain regions associated with dysfunctional responses, facilitates stress and cytokine-induced alcohol drinking in models of relapse, alters factors that can affect stress-induced expression of brain cytokines, and intensifies cytokine responses from neurons in the central amygdala (CeA) - a brain site that supports stress-induced negative affect. The innovative strategies to be undertaken will allow testing this hypothesis. Studies will first assess if adolescent and adult rats with differing CA exposures induce a common increase in the regional distribution cytokines in brain, but differing durations of the stress-induced increase in cytokine after CA. Subsequently, to test further that cytokines have a role in stress, determinations will define whether cytokines will substitute for stress facilitation of the alcohol deprivation effect (ADE) and enhancement of operant responding for alcohol. To explore possible means by which the degree of brain cytokines is increased by stress alone or after CA, investigations will determine if the alteration in the cytokine increase during stress alone and/or after CA exposure relates to CRF activity, to an indirect involvement of an endogenous agonist on TLR4 receptors, or to induction of HPA axis dysfunction. To explore neural actions of cytokines released by stress after CA, changes in neural excitability, pre-synaptic release of GABA and/or glutamate, as well as post-synaptic changes of CeA neurons by cytokines will be explored in controls and after CA exposure. A particularly innovative component is characterization of cell-types sensitive to actions of cytokines in the lateral or medial portions of the CeA with either oxytocin or vasopressin, respectively, and exploration of whether neural actions of cytokines on CeA neurons depend upon CRF. With these important processes to resolve issues concerning cytokine neuromediation in brain, a rational basis is expected to emerge that cytokine action initiated by stress after CA exposure contributes to the negative consequences associated with stress in the abstinent alcoholic. This innovative effort should be critical for redirecting the fous of drug discovery initiatives so that therapeutic approaches for treating alcohol abuse associated with stress can be improved.