Neurochemical Manipulation of Withdrawal-Induced Drinking

项目摘要 我们一直在使用遗传和环境控制相结合的方法来诱导高酒精摄入量 在小鼠中，定义为酒精摄入导致血液乙醇浓度(BEC)超过100 mg%。我们 确定间歇性接触乙醇蒸气和多次戒断发作(即MW组) 产生了高酒精摄入量和戒断症状，这与 这些动物对身体的依赖。这一过程被称为“戒断诱导饮酒”(WID)。 并被认为是依赖动物酒精摄入量增加的一种行为模型(也 被称为“依赖诱导”饮酒)。初步数据表明，氨基己酸酯(复合谷氨酸能 阿片受体拮抗剂纳曲酮可显著降低WID的表达。 随后的研究确定全身应用巴氯芬(GABAB受体激动剂)，MPEP (mGluR5拮抗剂)和NbI 27914(CRF1受体拮抗剂)显著降低血管内皮生长因子的表达。 太棒了。最后，杏仁体内注射CRF受体拮抗剂D-Phe-CRF(12-41)也是选择性的 减少MW组的高酒精摄入量，而不改变对照组的酒精摄入量。这个 目前的提案将继续使用WID模型进行这一调查，以确定关键的神经递质 和神经肽，调节WID的表达，并开始识别对 WID的表达式。我们假设杏仁核中央核的神经适应 (CEA)和外侧隔对WID的表达起重要作用。目标1将在药理上 操纵外侧隔的神经化学环境，而目标2将操纵 CEA的神经化学环境，以确定神经递质和神经肽 对小鼠高酒精摄入量和WID的表达具有重要意义。拟议中的研究将使用大脑部位- 特异的微量注射技术操纵大鼠的GABA能、谷氨酸能和CRF多肽环境 外侧隔和CEA。微量注射受体激动剂和拮抗剂将使我们能够确定 MW组和对照组对这些神经化学操作是否具有不同的敏感性 CEA和外侧隔，以及手法是否足以调节WID的表达。 总的来说，这项拟议的研究将检验高酒精背后的神经生物学机制。 消费WID表型。这些信息不仅有助于加深我们对 依赖诱导饮酒的潜在机制，但它也将有助于开发新的战略 用来治疗酒精中毒。项目叙事 这项拟议的研究将研究高酒精摄入背后的神经生物学机制 依附的动物。研究将使用脑部特定部位的微量注射技术来确定关键 调节依赖动物酒精摄入量增加的神经递质和神经肽 并开始辨别对酒精摄入量增加很重要的神经部位。这不仅会让你 信息有助于加深我们对依赖导致饮酒的潜在机制的理解， 但它也将有助于开发治疗酒精中毒的新策略。

Project Summary We have been using a combination of genetic and environmental manipulations to induce high ethanol intake in mice, defined as alcohol intake leading to a blood ethanol concentration (BEC) greater than 100 mg%. We determined that exposure to intermittent ethanol vapor and multiple withdrawal episodes (i.e., MW group) produced high ethanol consumption and withdrawal symptoms that were consistent with the development of physical dependence in these animals. This procedure has been termed "Withdrawal-Induced Drinking" (WID) and is thought to be one behavioral model of the increased alcohol consumption in dependent animals (also termed "dependence-induced" drinking). Preliminary data indicate that acamprosate (complex glutamatergic modulator), but not naltrexone (opioid receptor antagonist), significantly decreased the expression of WID. Subsequent studies determined that systemic administration of baclofen (GABAB receptor agonist), MPEP (mGluR5 antagonist), and NBI 27914 (CRF1 receptor antagonist) significantly decreased the expression of WID. Finally, intra amygdala administration of the CRF receptor antagonist D-Phe-CRF(12-41) also selectively decreased the high alcohol intake in the MW group without altering ethanol intake in the Control group. The present proposal will continue this line of inquiry with the WID model to determine the key neurotransmitters and neuropeptides that modulate the expression of WID and begin to discern neural sites that are important for the expression of WID. We hypothesize that neuroadaptations in the central nucleus of the amygdala (CeA) and lateral septum are important for the expression of WID. Aim 1 will pharmacologically manipulate the neurochemical environment of the lateral septum, whereas Aim 2 will manipulate the neurochemical environment of the CeA, to determine the neurotransmitters and neuropeptides that are important for the high alcohol intake and expression of WID in mice. Proposed studies will use a brain site- specific microinjection technique to manipulate the GABAergic, glutamatergic, and CRF peptide environment of the lateral septum and CeA. Microinjection of receptor agonists and antagonists will allow us to determine whether the MW and Control groups are differentially sensitive to these neurochemical manipulations of the CeA and lateral septum, and whether the manipulations are sufficient to modulate the expression of WID. Collectively, the proposed research will examine the neurobiological mechanisms underlying the high alcohol consumption WID phenotype. Not only will this information help in furthering our understanding of the mechanisms underlying dependence-induced drinking, but it also will aid in the development of new strategies for the treatment of alcoholism. Project Narrative The proposed research will examine the neurobiological mechanisms underlying high alcohol consumption in dependent animals. Studies will use a brain site-specific microinjection technique to determine the key neurotransmitters and neuropeptides that modulate the increased alcohol consumption in dependent animals and begin to discern neural sites that are important for this increased alcohol intake. Not only will this information help in furthering our understanding of the mechanisms underlying dependence-induced drinking, but it also will aid in the development of new strategies for the treatment of alcoholism.