Mechanisms of Amphetamine Withdrawal and Recovery

描述（由申请人提供）：拟议的研究将评估多巴胺能机制是否在引发安非他明引起的急性戒断症状中发挥作用。这将使用动物模型方法来完成。老鼠将被安置在可以长时间监测其行为的地方，它们将接受控制和药物治疗，并监测这些治疗对活动和食物摄入的影响。在大鼠中，中等剂量的安非他明在18至24小时后产生活动减退和吞咽减退，表明在此期间出现急性戒断。中等剂量的非选择性多巴胺激动剂阿波啡和中等剂量的D1和D2激动剂一起使用，但不能单独使用，都可以产生低活性。我们想知道同样的治疗是否会导致吞咽。结果不仅显示了这些症状对多巴胺能机制的依赖程度，而且还将开始揭示急性戒断症状是如何组织的：如果不同的症状对相同的治疗有相似的反应，那么这些症状的调解机制将被指出。否则，将显示分布式机制。除了这些操作外，我们还想看看在服用安非他明之前阻断多巴胺受体亚型是否可以预防活动不足。这一结果将证实安非他明在短期内通过促进D1和D2受体的相互作用而产生低活性。最后，我们将开始确定安非他明诱导的低活动和吞咽的表达是否由于多巴胺D1或D2受体数量的变化。为了做到这一点，我们将看到D1和D2受体的基因是如何在生理盐水和安非他明治疗后的不同时间在不同的大脑区域表达的，使用实时PCR。急性戒断与个人痛苦、生产力下降和药物复发风险增加有关：因此，预防和改善急性戒断是一个重要目标。只有确定引起症状的因素，才能控制急性戒断。拟议的研究将提供一种道德的、良好控制的、有效的方法来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): The proposed research will evaluate whether dopaminergic mechanisms play a role in the elicitation of symptoms of amphetamine-induced acute withdrawal. This will be done using an animal model approach. Rats will be housed in stations where behavior can be monitored for extended periods of time, they will receive control and drug treatments, and the effects of these treatments on activity and food intake will be monitored. In rats, moderate doses of amphetamine produce hypoactivity and hypophagia 18 to 24 hours later, suggesting that an acute withdrawal is present during that time. The hypoactivity can be produced by moderate doses of the nonselective dopamine agonist apomorphine and by moderate doses of D1 and D2 agonists given together, but not alone. We want to know if these same treatments can produce hypophagia. The results would not only show the degree of dependence of these symptoms on dopaminergic mechanisms, but would also begin to reveal how symptoms of acute withdrawal are organized: If different symptoms are similarly responsive to the same treatments, then mediation of these symptoms by a common mechanism would be indicated. Otherwise, distributed mechanisms would be indicated. In addition to these manipulations, we also want to see to see whether blocking either dopamine receptor subtype prior to amphetamine administration can prevent the hypoactivity. This result would confirm that amphetamine produces hypoactivity by promoting an interaction of D1 and D2 receptors in the short term. Finally we will begin to determine whether the expression of amphetamine-induced hypoactivity and hypophagia are due to a change in dopamine D1 or D2 receptor number. To do this we will see how genes for D1 and D2 receptors are expressed in different brain areas at different times after saline and amphetamine treatment, using real time PCR. 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.