Central Amygdala CART modulates ethanol withdrawal induced anxiety

杏仁核中央 CART 调节乙醇戒断引起的焦虑

• 批准号: 7547210
• 负责人: Armando Salinas
• 金额: $ 3.01万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7547210
• 关键词: Acute; Address; Alcohol consumption; Alcohol withdrawal syndrome; Amygdaloid structure; Animals; Anxiety; Behavior; Behavioral; Biological Assay; Blood; Brain region; CARTPT gene; Chronic; Convulsions; Corticosterone; Cues; Dependence; Development; Ethanol; Ethanol dependence; Glutamates; Hand; Hour; Hypothalamic structure; Immunohistochemistry; Individual; Knock-out; Knockout Mice; Lead; Lesion; Link; Measures; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurobiology; Neurons; Neuropeptides; Nucleus Accumbens; Paper; Peptides; Play; Preparation H; Proteins; Publications; Publishing; Rattus; Relapse; Reporting; Resistance; Role; Schedule; Serum; Spinal Cord; Stress; Synapses; Tail; Testing; Therapeutic Intervention; Time; Wild Type Mouse; Withdrawal; Work; acute stress; alcohol exposure; cost; disorder later incidence prevention; drinking; drug of abuse; experience; neurotransmission; novel; receptor expression; research study; response; restraint stress; social; stressor; success; voltage clamp

DESCRIPTION (provided by applicant): Ethanol dependence is a widespread affliction with societal costs in the hundreds of billions of dollars every year. Treatment of ethanol dependence is complicated by many factors, most notably relapse. Relapse behaviors are believed to result from ethanol withdrawal-induced anxiety (EWIA). A brain region critically involved in EWIA is the central amygdala (CeA). Lesions of the central, but not basolateral, amygdala resulted in reduced ethanol consumption during withdrawal. Neurobiological alterations induced by ethanol dependence are widespread; in the CeA, these changes include increased glutamatergic activity and NMDA receptor expression. During withdrawal, these increases lead to hyperactivation of the CeA; this hyperactivation is believed to mediate the withdrawal-induced anxiety that underlies relapse. Cocaine- and amphetamine-regulated transcript (CART) is a novel neuropeptide implicatied in ethanol dependence. It is expressed in the CeA and has been shown to increase expression here during acute withdrawal. Additionally, CART, has been reported to potentiate NMDA receptor-mediated currents. The overarching hypothesis of this proposal is that CART is a critical mediator of EWIA. To test this, a comprehensive examination of CART expression during dependence and withdrawal will be conducted. Ethanol dependence will-be induced using two models: chronic ethanol treatment (CET) and chronic intermittent ethanol (CIE). CIE contains a withdrawal component that presumably involves withdrawal induced anxiety. Dependence liability in wild type (WT) and CART knockout (KO) mice will compared using both CET and CIE. An examination of EWIA in the WT and KO mice at 0, 24, and 72 hours withdrawal will also be conducted. Corticosterone ELISAs and immunohistochemistry will be performed as well. Stress induced drinking and corticosterone levles in response to an acute stressor will also be assessed and compared between the WT and KO mice. The second half of this proposal will first verify in our hands, the NMDA potentiating actions of CART, specifically in the CeA. Then, a comprehensive electrophysiological voltage clamp analysis and comparison of NMDA receptor-mediated currents in the CeA of ethanol naive, CET, and CIE mice at 0, 24, and 72 hours withdrawal in WT and KO mice will be performed. The findings from these experiments will elucidate the underpinnings of EWIA and the role of CART in EWIA-induced relapse. Furthermore, these results will provide a novel target for therapeutic intervention and prevention of relapse in individuals dependent on ethanol and possibly other drugs of abuse.

描述（由申请人提供）：乙醇依赖是每年数千亿美元的社会成本的广泛苦难。乙醇依赖性的治疗因许多因素而复杂，最著名的是复发。人们认为复发行为是由乙醇戒断引起的焦虑（EWIA）引起的。在Ewia中关键的大脑区域是中央杏仁核（CEA）。杏仁核的中央病变（但不是基底外侧）导致撤离期间乙醇的消耗降低。乙醇依赖性引起的神经生物学改变是广泛的。在CEA中，这些变化包括增加的谷氨酸能活性和NMDA受体表达。在退出期间，这些增加导致CEA过度激活；据信这种过度激活可以介导戒断引起的焦虑，这是复发的基础。可卡因和苯丙胺调节的转录本（CART）是与乙醇依赖性有关的新型神经肽。它在CEA中表达，并已显示在急性戒断期间会增加表达。此外，据报道，CART可以增强NMDA受体介导的电流。该提议的总体假设是购物车是尤威亚的关键中介。为了测试这一点，将在依赖和戒断过程中对CART表达进行全面检查。乙醇依赖性使用两个模型诱导：慢性乙醇处理（CET）和慢性间歇性乙醇（CIE）。 CIE包含一个戒断成分，大概涉及戒断引起的焦虑。使用CET和CIE将比较野生型（WT）和CART敲除（KO）小鼠的依赖性责任。还将在0、24和72小时撤离时对WT和KO小鼠的EWIA检查。皮质酮ELISA和免疫组织化学也将进行。应力引起的饮酒和皮质酮左旋响应于急性应激源，并在WT和KO小鼠之间进行比较。该提案的后半部分将首先在我们手中验证，NMDA增强了推车的动作，特别是在CEA中。然后，将在WT和KO小鼠中进行全面的电生理电压夹分析和NMDA受体介导的电流在0、24和72小时退出的NMDA受体介导的电流。这些实验的发现将阐明Ewia的基础以及CART在EWIA诱导的复发中的作用。此外，这些结果将为依赖乙醇和其他可能滥用药物的个体的治疗干预和预防治疗性干预和预防复发提供新的目标。