Chronic alcohol affects stress-induced cytokines and cytokine neural function

描述(申请人提供)：在酗酒者戒酒期间，压力会导致HPA轴反应障碍，伴随着负面情绪的功能磁共振反应增加，并在复发时过量饮酒。尽管酗酒者的压力引起了这些事件，但这些易化的功能障碍反应的神经基础尚不清楚。在这方面，尽管促肾上腺皮质激素释放因子(CRF)被认为是慢性酒精(CA)后应激引起的功能障碍的原因，但一个被忽视的领域是，在戒酒过程中，细胞因子的应激增加也可能有助于这些应激效应的神经调节。本研究的目的是支持这样一种假设，即CA导致持续的神经适应不良，支持与功能障碍反应相关的特定脑区细胞因子的应激诱导，促进应激和细胞因子诱导的饮酒，改变可能影响应激诱导的脑细胞因子表达的因素，并增强中央杏仁核(CEA)神经元的细胞因子反应，中央杏仁核(CEA)是支持应激诱导的负面影响的大脑部位。将采取的创新战略将允许检验这一假设。研究将首先评估不同CA暴露的青春期和成年大鼠是否在CA后诱导脑内局部分布细胞因子的共同增加，但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取代酒精剥夺效应(ADE)的应激促进作用和增强对酒精的操纵性反应。为了探索单独应激或CA后脑细胞因子水平增加的可能途径，研究将确定在应激单独和/或CA暴露后细胞因子水平的变化是否与CRF活性有关，是否与TLR4受体上的内源性激动剂间接参与，或与诱导HPA轴功能障碍有关。为了探讨CA后应激释放的细胞因子的神经作用，我们将观察对照组和CA暴露后神经细胞兴奋性、突触前GABA和/或谷氨酸释放的变化以及细胞因子对CEA神经元突触后的影响。一个特别创新的部分是表征CEA外侧部分或内侧部分对细胞因子分别与催产素或加压素的作用敏感的细胞类型，并探索细胞因子对CEA神经元的神经作用是否依赖于CRF。有了这些重要的过程来解决大脑中细胞因子的神经调节问题，一个合理的基础有望出现，即CA暴露后应激启动的细胞因子作用有助于戒酒者与应激相关的负面后果。这一创新努力对于改变药物发现计划的重点至关重要，以便改善治疗与压力有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.