Mechanisms of Amphetamine Withdrawal and Recovery

说明（由申请人提供）：在消遣性药物使用中，偶尔会使用高剂量但无毒的药物。当大鼠按照这种方式服用安非他明时，在服用药物后大约18至24小时会出现急性戒断综合征。观察到的症状包括活动减退和吞咽不足。总的研究目标是了解这种安非他明引起的急性戒断综合征。与过去的奖励期一样，将寻求引起不同症状的条件的基本信息，并评估有关机制的假设。但除此之外，如何组织急性戒断综合征的症状的新理论将被探索。根据这一理论，证候被组织成症状群，即相互关联的不同症状组。在大多数拟议的实验中，老鼠将被安置在可以连续监测其活动或食物摄入的站点。在几项拟议的研究中，将把症状分组的临时标准应用于活动不足和吞咽不足，以评估它们是否属于同一症状群的组成部分。例如，如果不同剂量的安非他明对活动不足和吞咽不足产生相似的效果，那么根据一个标准，这些症状应该分组。在其他实验中，以这种方式设想戒断综合症的一些含义将被评估。在一项研究中，一个假定的症状簇的时间依赖性变化将用于指导寻找潜在分子介质的时间选择。在最后的研究中，方法和概念将应用于另一类药物吗啡产生的急性戒断。拟议研究中使用的方法与根据可观察到的行为和神经生物学测量对精神障碍进行分类的倡议是一致的，而不是根据症状的表现。由于所讨论的理论将综合征的基本单位视为一组症状，因此它对诊断和治疗具有重要意义。

DESCRIPTION (provided by applicant): In recreational drug use, high but non toxic doses of a drug are occasionally administered. When rats are administered amphetamine according to this kind of regime, an acute withdrawal syndrome occurs approximately 18 to 24 hours after drug receipt. Hypoactivity and hypophagia are among the symptoms observed. The overall research goal is to understand this amphetamine-induced acute withdrawal syndrome. As in past award periods, basic information about the conditions that elicit different symptoms will be sought, and hypotheses about mechanisms involved will be assessed. But in addition, a new theory of how the symptoms of the acute withdrawal syndrome are organized will be explored. According to this theory, the syndrome is organized into symptom clusters, that is, different groups of interrelated symptoms. In most of the proposed experiments, rats will be housed in stations where either activity or food intake can be continuously monitored. In several of the proposed studies, provisional criteria for grouping symptoms will be applied to hypoactivity and hypophagia, in order to assess whether they are components of the same symptom cluster. For example, if different doses of amphetamine produce comparable effects on hypoactivity and hypophagia, then by one criterion the symptoms should be grouped. In other experiments some of the implications of conceiving of the withdrawal syndrome in this way will be assessed. In one study, time-dependent changes in a putative symptom cluster will be used to guide the selection of times at which to look for potential molecular mediators. In a final study, the methodology and conceptualizations will be applied to the acute withdrawal produced by a drug from another class, morphine. The approach used in the proposed studies is consistent with initiatives to classify mental disorders on the basis of observable behaviors and neurobiological measures, rather than on the basis of presenting symptoms. Because the theory under discussion views the fundamental unit of a syndrome as a cluster of symptoms, it has significant implications for diagnosis and treatment. PUBLIC HEALTH RELEVANCE: Acute withdrawal is associated with personal distress, decreased productivity, and increased risk of drug relapse: Consequently, preventing and ameliorating acute withdrawal is an important objective. Acute withdrawal can be managed only if the factors that give rise to the symptoms can be identified. The proposed research will provide an ethical, well controlled, and efficient means for identifying the brain and body factors that contribute to acute withdrawal and for evaluating potential treatments.