Cocaine, Electroconvulsive Seizure and Neural Plasticity

描述（由申请人提供）：我们推测可卡因和其他药物成瘾的持久性可能是由于药物引起的变化，最终导致与渴望和复发有关的特定大脑区域的可塑性丧失。一个治疗可卡因成瘾的新概念是，在个体学习远离毒品的时期（消退阶段），神经可塑性的恢复可能会防止寻求毒品或吸毒行为的复发。本研究的重点是通过控制药物寻求行为的消退期，为抑制复发提供一个新的框架。因此，我们可以利用一个关键的窗口期，在此期间，学习避免药物寻求/服用可能会通过同时诱导神经可塑性而增强。电痉挛疗法（ECT）或癫痫（ECS）现在被认为是治疗严重抑郁症的成功方法，因为它能够增加大脑中的神经可塑性。被认为参与ecs诱导的可塑性的关键分子是生长因子。由于消失是一种新的学习过程，在可卡因诱导的条件位置偏好（CPP）消失阶段，生长因子的改变可能会减少大鼠药物寻求行为的恢复。我们的研究表明，与对照组相比，在消退阶段给予ECS可以抑制可卡因启动CPP的恢复。在消退阶段之前进行相同的ECS治疗并没有改变恢复。这些研究的主要目标是优化ECS治疗的参数，以最大限度地抑制可卡因启动恢复。提出的研究主要基于这样的假设，即在消退阶段给予ECS治疗对抑制可卡因启动恢复最有效。具体目标1将确定癫痫发作持续时间和ECS治疗天数对恢复可卡因启动CPP的影响。在ECS治疗过程中，通过改变脉冲剂量、ECS持续时间和麻醉深度，可以改变癫痫发作的持续时间。特异性目标2将优化ECS治疗的时机，以抑制可卡因诱发CPP的恢复。ECS的时间将被转移到消光期之前、期间或之后。该Aim还将测试相对于消退的ECS时间（以小时为单位），以确定ECS的时间对抑制恢复是否重要。我们的研究表明，在人类身上使用电痉挛疗法可能是治疗可卡因成瘾的一种方法，就像治疗人类严重抑郁症一样。然而，我们的长期兴趣是了解ECS的关键神经生物学后果，这可能导致可卡因成瘾的治疗。

DESCRIPTION (provided by applicant): We speculate that the long-lasting nature of cocaine and other drug addiction may be due to drug-induced changes that ultimately produce a loss of plasticity in specific brain regions involved with craving and relapse. A novel conceptualization for the treatment of cocaine addiction is that restoration of neural plasticity during the period when the individual is learning to stay away from drugs (the extinction phase) may prevent relapse to drug-seeking or drug-taking behavior. The proposed studies focus on providing a new framework for suppressing relapse by manipulating the extinction period of drug-seeking behavior. Thus, we may take advantage of a critical window during which learning to avoid drug seeking/taking may be enhanced by simultaneous induction of neural plasticity. Electroconvulsive therapy (ECT) or seizure (ECS) is now viewed as successful in treating severe depression because of its ability to increase neural plasticity in the brain. Key molecules thought to be involved in ECS-induced plasticity are growth factors. Because extinction is new learning, alteration of growth factors during the extinction phase of cocaine-induced conditioned place preference (CPP) may reduce the reinstatement of drug-seeking behavior in rats. Our studies show that ECS given during the extinction phase suppresses reinstatement of cocaine-primed CPP compared with controls. The same ECS treatments delivered prior to the extinction phase did not alter reinstatement. The primary goal of these studies is to optimize the parameters of ECS treatment to produce maximal suppression of cocaine-primed reinstatement. The proposed studies center on the main hypothesis that ECS treatment is most effective in suppressing cocaine-primed reinstatement when given during the extinction phase. Specific Aim 1 will determine the effects of seizure duration and number of days of ECS treatment on reinstatement of cocaine-primed CPP. Seizure duration will be altered by changing the pulse dose and duration of ECS and depth of anesthesia during ECS treatments. Specific Aim 2 will optimize the timing of ECS treatment for its ability to suppress reinstatement of cocaine-primed CPP. The timing of ECS will be shifted to before, during or after the extinction phase. This Aim will also test ECS timing (in hours) relative to extinction to determine if the timing of ECS is important for the suppression of reinstatement. Our studies indicate that ECT in humans may be an option for some cases of cocaine addiction, as it is for severe depression in humans. However, our long term interest is to understand the critical neurobiological consequences of ECS that could lead to treatment for cocaine addiction.