SEROTONERGIC CHARACTERIZATION OF ETHANOL WITHDRAWAL

这项提案寻求扩大乙醇特性的实验 戒断的症状和机制。滥用 乙醇产生依赖，其特征是戒断模式 由诸如焦虑等主观症状组成。尽管关键角色是 在引发和维持酒精滥用的这些症状中， 认识到，动物对主观症状的研究已经 很难。在本供资期间，有证据表明 停用乙醇会产生类似PTZ的内部刺激，可用于 产生关于戒断的主观症状的参数数据。这个 在酒精戒断过程中发生的类赫兹刺激被 作用于γ-氨基丁酸A型受体的药物- 氯离子通道复合体。然而，PTZ-IDS对 脑内5-羟色胺(5HT)系统的调节。5HT系统已经被 与酒精依赖有牵连，在我们自己身上也很重要 采用其他行为措施的实验。为了更好地 5-羟色胺在酒精依赖和酒精依赖形成过程中的作用 戒毒使用歧视药物的方法，新的实验是 建议使用5-羟色胺激动剂1(3-氯苯基)哌嗪，mCPP，AS 一种歧视性刺激，用于描述一种动物模型 戒断症状。建议：1)证明mCPP入侵检测系统 在动物体内是由药物调节的，这些药物要么会引起焦虑，要么会 人类中的抗焦虑药，2)展示和描述自发的 酒精戒断过程中mCPP样刺激的发生与 作为累积乙醇的函数的刺激强度 剂量，3)用选定的5-羟色胺受体修饰戒断刺激 亚型激动剂和拮抗剂，以及4)比较和对比PTZ 和mCPP刺激，以确定酒精戒断的方式 5-羟色胺和GABA系统在产生 “焦虑”样的行为。该方法的使用将提供重要的新的 数据，并扩展在我们的其他动物模型中获得的结果 焦虑。这项研究具有重要意义，因为它提供了信息 与酒精滥用的病因和治疗直接相关。

This proposal seeks to expand experiments on characterizing ethanol withdrawal with respect to its symptoms and their mechanisms. Abuse of ethanol produces dependence characterized by a pattern of withdrawal consisting of subjective symptoms such as anxiety. Although the key role of these symptoms in initiating and maintaining ethanol abuse is well recognized, animal research on the subjective symptoms has been difficult. In the current funding period, it was demonstrated that ethanol withdrawal produces a PTZ-like internal stimulus that can be used to produce parametric data on the subjective symptoms of withdrawal. The HZ-like stimulus occurring during ethanol withdrawal was modulated by drugs acting at the gamma-amino butyric acid-type A (GABAA) receptor- chloride ion channel complex. However, PTZ-IDS was insensitive to modulation of brain serotonin (5HT) systems. The 5HT systems have been implicated in ethanol dependence and found important in our own experiments employing other behavioral measures. In order to better characterize the role of 5HT in the development of ethanol dependence and withdrawal using drug discrimination approach, new experiments are proposed to employ a 5HT agonist, 1(3-chlorophenyl)piperazine, mCPP, as a discriminative stimulus to characterize an animal model of the withdrawal symptoms. It is proposed: 1) to demonstrate that the mCPP IDS in animals is modulated by drugs which are either anxiogenic or anxiolytic in humans, 2) to demonstrate and characterize the spontaneous occurrence of a mCPP-like stimulus during ethanol withdrawal in relation to the intensity of the stimulus as a function of cumulative ethanol dose, 3) to modify the withdrawal stimulus by selected 5HT receptor subtype agonists and antagonists, and 4) to compare and contrast the PTZ and mCPP stimuli during ethanol withdrawal to determine the manner in which the 5HT and GABA systems relate to one another in producing "anxiety"-like behavior. Use of this method will provide important new data and extend the results obtained in our other animal models of anxiety. This research is significant because it provides information directly related to etiology and treatment of ethanol abuse.