Mechanisms of Amphetamine Withdrawal and Recovery

描述（由申请人提供）：在娱乐性药物使用中，偶尔会给予高剂量但无毒的药物。当根据这种方案给大鼠施用安非他明时，在接受药物后约18至24小时发生急性戒断综合征。观察到的症状包括活动减退和食欲减退。总体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，将寻求有关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，一个关于急性戒断综合征的症状是如何组织的新理论也将被探索。根据这一理论，综合征被组织成症状群，即相互关联的不同症状组。在大多数拟议的实验中，大鼠将被安置在可以连续监测活动或食物摄入的站中。在几项拟议的研究中，将对活动减退和食欲减退应用临时症状分组标准，以评估它们是否属于同一症状群。例如，如果不同剂量的安非他明对活动减退和食欲减退产生类似的影响，那么就应该根据一个标准对症状进行分组。在其他实验中，我们将评估以这种方式构想戒断综合征的一些含义。在一项研究中，一个假定的症状群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，方法和概念将被应用于急性戒断所产生的药物从另一个类别，吗啡。在拟议的研究中使用的方法是一致的倡议，以可观察到的行为和神经生物学措施的基础上，而不是在呈现症状的基础上对精神障碍进行分类。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。 公共卫生相关性：急性戒断与个人痛苦、生产力下降和药物复吸风险增加有关：因此，预防和改善急性戒断是一个重要的目标。只有在能够确定引起症状的因素的情况下，才能对急性戒断进行管理。拟议的研究将提供一种符合伦理的、控制良好的、有效的手段，用于识别导致急性戒断的大脑和身体因素，并评估潜在的治疗方法。

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.