Chronic alcohol affects stress-induced cytokines and cytokine neural function

慢性酒精影响应激诱导的细胞因子和细胞因子神经功能

• 批准号: 8803746
• 负责人: GEORGE R BREESE
• 金额: $ 26.92万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-10 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803746
• 关键词: Abstinence; Address; Adolescent; Adrenal Glands; Adult; Affect; Agonist; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Amygdaloid structure; Anxiety; Area; Behavior; Behavioral; Biochemical; Brain; Brain region; Chronic; Chronic stress; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Data; Evaluation; Event; Figs - dietary; Functional Magnetic Resonance Imaging; Functional disorder; Glucocorticoid Receptor; Glutamates; Goals; Health; Hypothalamic structure; Immune; Investigation; Kindling (Neurology); Knowledge; Lateral; Link; Medial; Modeling; Neurobiology; Neurons; Neurophysiology - biologic function; Oxytocin; Pituitary Gland; Process; Rattus; Regulation; Relapse; Reporting; Research; Role; Site; Stress; Synapses; TNF gene; Testing; Therapeutic; Tumor Necrosis Factor-alpha; Vasopressins; Withdrawal; Work; alcohol abstinence; alcohol exposure; alcohol seeking behavior; base; behavioral response; cell type; clinical investigation; cytokine; deprivation; drinking; drug discovery; gamma-Aminobutyric Acid; hypothalamic-pituitary-adrenal axis; improved; innovation; neuroadaptation; neuropathology; novel; prevent; problem drinker; receptor; relating to nervous system; response; social; synaptic function; toll-like receptor 4; underage drinking; withdrawal-induced anxiety

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.

描述（由申请人提供）：在戒酒期间，压力导致HPA轴反应功能失调，fMRI反应增加，伴有负面情绪，复发后过量饮酒。尽管这些记录良好的事件是由酗酒者的压力引起的，但这些促进功能失调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）被认为有助于慢性酒精（CA）后应激诱导的功能障碍，但一个被忽视的领域是细胞因子的应激增加也可能有助于戒断期间应激的这些影响的神经中介。本研究的目的是为以下假设提供支持，即CA诱导持续的神经适应不良，支持与功能失调反应相关的选定脑区域的细胞因子的应激诱导，促进复发模型中的应激和细胞因子诱导饮酒，改变影响应激诱导的脑细胞因子表达的因素。并加强来自中央杏仁核（CeA）神经元的细胞因子反应，这是大脑中支持压力引起的负面影响的部位。将要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会诱导大脑区域分布细胞因子的共同增加，但CA后应激诱导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会替代酒精剥夺效应（ADE）的应激促进和对酒精的操作反应的增强。为了探索单独应激或CA后脑细胞因子程度增加的可能途径，研究将确定单独应激和/或CA暴露后细胞因子增加的改变是否与CRF活性，内源性激动剂对TLR4受体的间接参与，或诱导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，我们将在对照和CA暴露后探讨细胞因子对神经兴奋性、GABA和/或谷氨酸突触前释放以及CeA神经元突触后变化的影响。一个特别创新的部分是分别用催产素或加压素表征对CeA外侧或内侧部分细胞因子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。通过这些重要的过程来解决大脑中有关细胞因子神经调节的问题，一个合理的基础有望出现，即CA暴露后应激引发的细胞因子作用有助于戒酒者应激相关的负面后果。这种创新的努力对于重新定向药物发现倡议的重点至关重要，以便改进治疗与压力有关的酒精滥用的治疗方法。