Neurochemical Manipulation of Withdrawal-Induced Drinking

描述(申请人提供)：我们一直在使用遗传和环境操作的组合来诱导小鼠高酒精摄入量，定义为酒精摄入量导致血液乙醇浓度(BEC)大于100 mg%。我们确定，间歇性乙醇蒸气暴露和多次戒断(即MW组)会产生高酒精消耗量和戒断症状，这与这些动物的身体依赖的发展是一致的。这个过程被称为“戒断诱导饮酒”(WID)，被认为是依赖动物酒精摄入量增加的一种行为模式(也称为“依赖诱导”饮酒)。初步数据表明，阿卡米松(复合谷氨酸能调节剂)可显著降低WID的表达，而阿片受体拮抗剂纳曲酮则无此作用。随后的研究发现，全身应用巴氯芬(GAAB受体激动剂)、MPEP(mGluR5拮抗剂)和NBI 27914(CRF1受体拮抗剂)可显著降低WID的表达。最后，杏仁体内注射CRF受体拮抗剂D-Phe-CRF(12-41)也选择性地减少MW组的高酒精摄入量，而不改变对照组的酒精摄入量。本研究将继续用WID模型进行这一探索，以确定调节WID表达的关键神经递质和神经肽，并开始辨别对WID表达重要的神经部位。我们假设杏仁中央核(CEA)和外侧隔核的神经适应性对WID的表达是重要的。目的1将从药物上操纵外侧隔的神经化学环境，而目的2将操纵CEA的神经化学环境，以确定对小鼠高酒精摄入和WID表达起重要作用的神经递质和神经肽。拟议的研究将使用脑部位特异性微量注射技术来操纵外侧隔和CEA的GABA能、谷氨酸和CRF多肽环境。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CEA和外侧隔的这些神经化学操作是否有不同的敏感性，以及这些操作是否足以调节WID的表达。总而言之，这项拟议的研究将检查高饮酒WID表型背后的神经生物学机制。这些信息不仅将有助于我们进一步了解导致饮酒依赖的潜在机制，而且还将有助于开发治疗酒精中毒的新策略。公共卫生相关性这项拟议的研究将研究依赖动物大量饮酒的神经生物学机制。研究将使用大脑部位特异性微量注射技术来确定调节依赖动物酒精摄入量增加的关键神经递质和神经肽，并开始识别对酒精摄入量增加至关重要的神经部位。这些信息不仅将有助于我们进一步了解导致饮酒依赖的潜在机制，而且还将有助于开发治疗酒精中毒的新策略。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE 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.