Neural Sensitivity to Stress During Drug Withdrawal

描述（由申请人提供）：在从精神兴奋剂（如可卡因或安非他明）戒断期间暴露于压力事件，在动物模型和人类个体中都会引起药物渴望和药物复发。精神兴奋剂戒断后，压力对药物寻求行为的影响持续数月，并在与精神兴奋剂成瘾相关的慢性复发中发挥重要作用。正是精神兴奋剂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。确定在精神兴奋剂停药期间发生的神经系统改变将对预防药物复发的药理学治疗的发展产生重大影响。本提案概述的研究将确定滥用精神兴奋剂是否会导致与压力相关的神经系统的敏感性增加。这些研究还将确定在精神兴奋剂戒断期间这些影响的持续时间。这将通过使用精神兴奋剂戒断的实验室大鼠模型来实现。应激行为的改变，以及调节应激行为的神经递质系统活动的改变，将在急性和长期戒断安非他明期间确定。此外，研究将确定精神兴奋剂戒断后神经应激系统和应激行为的改变是否可以通过抗抑郁药氟西汀的长期治疗逆转。综上所述，本实验将阐明精神兴奋剂戒断期间应激敏感性的神经基础，并将确定抗抑郁药物治疗减少应激行为从而减少精神兴奋剂复发的可行性。

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.