Research Component 2: Breese

研究部分 2：Breese

• 批准号: 7496828
• 负责人: GEORGE R BREESE
• 金额: $ 26.15万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7496828
• 关键词: Adolescent; Adult; Alcohol abuse; Alcohol withdrawal syndrome; Alcoholism; Anxiety; Behavior; Behavioral; Brain; CCL2 gene; Chronic; Data; Diet; Dose; Ethanol; Exposure to; Flumazenil; Foundations; Future; Human; Membrane; Nature; Neurotransmitters; Pathology; Peptides; Pharmaceutical Preparations; Predisposition; Probability; Protocols documentation; Rattus; Relapse; Research; Standards of Weights and Measures; Stress; Support System; System; Testing; Withdrawal; Work; base; caN protocol; cytokine; day; drinking; inhibitor/antagonist; insight; neurochemistry; neuromechanism; novel; prevent; problem drinker; receptor; relating to nervous system; therapy development; underage drinking

Research Component 2 - Breese "Persistent Sensitization of Ethanol Withdrawal Behavioral Pathology by Cvtokines". Following chronic ethanol, a-MSH, a peptide known to antagonize cytokines, is reduced. Based upon know-ledge that stress increases cytokines in brain, it was considered that sensitization of withdrawalinduced anxiety-like behavior (anxiety) following repeated stresses prior to a single 5 day exposure to ethanol (ETOH) diet (stress/withdrawal protocol) could involve cytokines. When two doses of lipopolysaccaride (IPS) were administered at weekly intervals [instead of stress] to increase brain cytokines prior to ETOH diet (IPS/withdrawal protocol), sensitization of withdrawal-induced anxiety was observed. Likewise, repeated ICV dosing of selected cytokines prior to ETOH (cytokine/withdrawal protocol) also sensitized withdrawal-induced anxiety. The sensitization induced by the LPS/withdrawal protocol was blocked by flumazenil, a result common with the repeated withdrawal and stress/withdrawal protocols. With re-instatement to 5 days of ETOH 16 days after initial exposure to the LPS/cytokine/withdrawal protocols sensitizing withdrawal-induced anxiety, it was apparent that cytokines could induce a sustained adaptive change just as observed with the other standard protocols. Based upon these Preliminary findings, it is hypothesized that the cytokine/withdrawal protocol is accompanied by adaptive changes that are supported by neurochemical systems common with the stress/withdrawal and the repeated withdrawal protocols. To explore this hypothesis, Aim 1 will determine if adaptations other than sensitization of withdrawal-induced anxiety found after the repeated withdrawal and the LPS/withdrawal protocols are common with the cytokine/withdrawal protocol. These other adaptive changes include a neural increase in the a4-GABAA receptor subunit, an increase in the duration of expression of CCL2 (MCP1) induced by LPS, and sensitization of stress-induced anxiety and cytokine expression. Aim 2 continues to seek commonality of the cytokine/withdrawal protocol by defining whether drugs that block sensitization of withdrawal associated with the repeated withdrawal and the stress/withdrawal protocols have a like effect on the sensitization associated with the cytokine/withdrawal protocol. Because adolescent drinking increases the probability for later alcoholism, Aim 3 tests whether adolescents are more vulnerable to the effects of the cytokine/withdrawal protocol than rats treated as adults. Completion of these Aims will provide new insight into the possible involvement of cytokines in the adaptive changes common with the stress/withdrawal and the repeated withdrawal protocols. Documenting such involvement of cytokines in adaptive changes induced by chronic ETOH could have relevance to the vulnerability alcoholics have for relapse to drinking and could provide a novel avenue for future development of treatments to disrupt the persistent adaptive pathology responsible for sustaining alcoholism.

研究成分2-布雷斯（Breese）“通过 cvtokines”。基于慢性乙醇后，慢性乙醇A-MSH，一种已知可拮抗细胞因子的肽。 知道压力会增加大脑的细胞因子，因此被认为是戒断诱导的敏感性 在一次5天之前重复应力后，焦虑状行为（焦虑） 乙醇（ETOH）饮食（压力/戒断方案）可能涉及细胞因子。当两剂 每周（而不是压力）施用脂多多亚菌（IPS），以增加脑细胞因子 在ETOH饮食（IPS/戒断方案）之前，观察到戒断诱导的焦虑的敏化。 同样，在ETOH之前重复对选定细胞因子的ICV给药（细胞因子/戒断方案）也 敏感的戒断引起的焦虑。 LPS/撤回方案引起的敏化是 被flumazenil阻塞，结果是反复撤回和压力/戒断方案。和 初次接触LPS/细胞因子/提取方案后16天重新添加到ETOH的5天 敏感提取引起的焦虑，很明显细胞因子可以诱导持续的适应性 与其他标准协议观察到的更改一样。基于这些初步发现，这是 假设细胞因子/提取方案伴随着支持的自适应变化 通过与压力/戒断和反复撤回方案相同的神经化学系统。到 探索这一假设，目标1将确定除了提高戒断诱导以外的适应 反复戒断和LP/撤回方案后发现的焦虑很常见 细胞因子/提取方案。这些其他自适应变化包括A4-GABAA的神经增加 受体亚基，LPS诱导的CCL2（MCP1）表达持续时间的增加， 压力诱导的焦虑和细胞因子表达的敏化。 AIM 2继续寻求共同点 细胞因子/提取方案是否通过定义阻止与戒断敏化的药物相关的药物 反复的撤回和压力/撤回方案对敏化有同样的影响 与细胞因子/提取方案相关联。因为青少年饮酒增加了 后来的酒精中毒，AIM 3测试青少年是否更容易受到影响 细胞因子/戒断方案比被视为成人的大鼠。这些目标的完成将提供新的见解 在压力/戒断和 重复的撤回协议。记录细胞因子在自适应变化中的参与 由慢性EtoH诱导 并可以为未来开发治疗的途径提供新的途径，以破坏持续的适应性 负责维持酒精中毒的病理学。