Neural Sensitivity to Stress During Drug Withdrawal

描述(由申请人提供)：在戒除可卡因或安非他明等精神刺激剂的过程中，暴露在应激事件中，在动物模型和人类个体中都会导致药物渴求和药物复发。在心理刺激戒除后，压力对寻求药物行为的影响持续了几个月，并在与心理刺激成瘾相关的慢性复发中发挥了很大作用。正是精神刺激性成瘾和复发的慢性性质产生了重大的社会、健康和经济影响。确定在精神刺激剂停药期间发生的神经变化将对旨在防止药物复发的药物治疗的发展产生重大影响。这项提案概述的研究将确定精神刺激剂滥用是否会导致与压力相关的神经系统的敏感性增加。这些研究还将确定这些影响在精神刺激剂停药期间的持续时间。这将通过使用精神刺激剂戒断的实验室大鼠模型来实现。应激行为的变化，以及调节应激行为的神经递质系统的活动的变化，将在急性和长期停用苯丙胺期间确定。此外，研究将确定精神刺激剂停药后神经应激系统和应激行为的变化是否可以通过长期治疗抗抑郁剂氟西汀来逆转。总之，拟议的实验将阐明精神刺激剂停药期间应激敏感性的神经基础，并将确定抗抑郁治疗的可行性，以减少应激行为，从而减少精神刺激剂的复发。

DESCRIPTION (provided by applicant): Exposure to stressful events during withdrawal from psychostimulants, such as cocaine or amphetamine, induces drug craving and drug relapse in both animal models and human individuals. The effects of stress on drug-seeking behavior persist for months following psychostimulant abstinence, and play a large part in chronic relapses associated with psychostimulant addiction. It is the chronic nature of psychostimulant addiction and relapse that produces significant social, health and economic impact. Identifying the neurological alterations that occur during psychostimulant withdrawal will have significant impact on the development of pharmacological treatments designed to prevent drug relapse. The studies outlined by this proposal will determine whether psychostimulant abuse results in increased sensitivity of stress-related neural systems. These studies will also establish the duration of these effects during psychostimulant withdrawal. This will be achieved by using laboratory rat models of psychostimulant withdrawal. Changes in stress behavior, and alterations to the activity of neurotransmitter systems that regulate stress behavior, will be determined during acute and protracted withdrawal from amphetamine. Furthermore, studies will determine whether alterations to neural stress systems and stress behavior following psychostimulant withdrawal can be reversed by chronic treatment of the antidepressant, fluoxetine. Together, the proposed experiments will elucidate the neural substrates of stress sensitivity during psychostimulant withdrawal, and will determine the feasibility of antidepressant treatment to reduce stress behaviors and thus psychostimulant relapse.