Neural Sensitivity to Stress During Drug Withdrawal

描述（由申请方提供）：在动物模型和人类个体中，在从精神兴奋剂（如可卡因或安非他明）戒断期间暴露于应激事件会诱导药物渴望和药物复发。精神刺激剂戒断后，压力对寻求药物行为的影响持续数月，并在与精神刺激剂成瘾相关的慢性复发中发挥很大作用。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。确定精神兴奋剂戒断过程中发生的神经系统变化将对旨在预防药物复吸的药物治疗的发展产生重大影响。该提案概述的研究将确定精神兴奋剂滥用是否会导致与压力相关的神经系统敏感性增加。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。应激行为的变化，以及调节应激行为的神经递质系统活性的改变，将在急性和长期戒断安非他明期间确定。此外，研究将确定是否改变神经应激系统和应激行为后，精神兴奋剂戒断可以逆转长期治疗的抗抑郁药，氟西汀。总之，拟议的实验将阐明精神兴奋剂戒断过程中压力敏感性的神经基质，并将确定抗抑郁治疗的可行性，以减少压力行为，从而精神兴奋剂复发。

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.