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）：酗酒者戒酒期间，压力会导致 HPA 轴反应功能失调、fMRI 反应增加并伴有负面情绪，以及复发时过量饮酒。尽管酗酒者的压力诱发了这些有据可查的事件，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）被认为会导致慢性酒精（CA）后应激引起的功能障碍，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酒期间应激影响的神经介导。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，支持与功能失调反应相关的选定大脑区域中细胞因子的应激诱导，促进复发模型中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，并增强中枢神经元的细胞因子反应 杏仁核（CeA）——支持压力引起的负面情绪的大脑部位。将采取的创新策略将能够检验这一假设。研究将首先评估不同CA暴露的青少年和成年大鼠是否会导致大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会替代应激促进的戒酒效应（ADE）和增强对酒精的操作反应。为了探索单独应激或 CA 后脑细胞因子程度增加的可能方式，研究将确定单独应激期间和/或 CA 暴露后细胞因子增加的变化是否与 CRF 活性、内源性激动剂对 TLR4 受体的间接参与有关，或与 HPA 轴功能障碍的诱导有关。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，以及细胞因子对 CeA 神经元的突触后变化。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取决于 CRF。通过这些重要的过程来解决大脑中细胞因子神经介导的问题，预计会出现一个合理的基础，即 CA 暴露后压力引发的细胞因子作用导致了与戒酒者压力相关的负面后果。这项创新努力对于重新调整药物发现计划的重点至关重要，以便改进治疗与压力相关的酗酒的治疗方法。