SEROTONERGIC CHARACTERIZATION OF ETHANOL WITHDRAWAL

乙醇戒断的血清素特征

• 批准号: 2429250
• 负责人: HARBANS LAL
• 金额: $ 14.74万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-06-01 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2429250
• 关键词: anxiety; avoidance behavior; behavior test; benzodiazepines; biological models; chordate locomotion; drug interactions; drug withdrawal; ethanol; gamma aminobutyrate; laboratory rat; neurobiology; neurochemistry; neuropharmacology; open field behavior; operant conditionings; pentylenetetrazole; piperazines; psychopharmacology; reinforcer; serotonin; serotonin inhibitor; serotonin receptor; stimulant /agonist; stimulus generalization

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.

该建议旨在扩大有关乙醇表征的实验 在其症状及其机制方面提取。滥用 乙醇产生的依赖性为特征，其特征是戒断模式 由焦虑等主观症状组成。虽然关键角色 在发起和维持滥用乙醇的症状中很好 认识到主观症状的动物研究已经 难的。在当前的资金期间，已经证明 乙醇提取产生可以使用的类似PTZ的内部刺激 产生有关戒断的主观症状的参数数据。这 在提取乙醇期间发生的Hz样刺激受到调节 作用于γ-氨基丁酸丁酸型A（GABAA）受体的药物 - 氯离子通道复合物。但是，PTZ-ID对 调节脑血清素（5HT）系统。 5HT系统已经 与乙醇的依赖有关，并在我们自己身上很重要 采用其他行为措施的实验。为了更好 表征5HT在乙醇依赖性发展中的作用和 使用药物歧视方法提取，新实验是 提议采​​用5HT激动剂，1（3-氯苯基）哌嗪，MCPP，AS 一种歧视性刺激，以表征 戒断症状。建议：1）证明MCPP ID 在动物中，动物受到抗焦虑或 人类中的抗焦虑，2）证明和表征自发的 在乙醇退出期间发生的MCPP样刺激发生 达到刺激的强度，累积乙醇的函数 剂量，3）通过选定的5HT受体修改戒断刺激 亚型激动剂和拮抗剂，以及4）比较和对比PTZ 在乙醇提取期间的MCPP刺激以确定 5HT和GABA系统在生产中相互关联 “焦虑”类似行为。使用此方法将提供重要的新 数据并扩展在我们的其他动物模型中获得的结果 焦虑。这项研究很重要，因为它提供了信息 与乙醇滥用的病因和治疗直接相关。