Involvement of protracted withdrawl in morphine relapse

描述（由申请人提供）： 许多药物滥用者成功地在几天到几个月内摆脱了毒品，但其中大多数人在急性身体戒断后很长时间内经历了持续的渴望和复发，这一时期被称为长期戒断。这些结果表明，以前对药物的接触和依赖会导致长期变化，影响随后的药物偏好和寻求。最近，我们的实验室发现，大鼠依赖于吗啡通过颗粒植入，然后退出5周显示出增强的偏好吗啡相比，安慰剂颗粒植入动物时，在条件性位置偏好范式测试。我们的实验室还发现，腹侧去甲肾上腺素能束，它携带的信息从髓质去甲肾上腺素能神经元的床核的终纹（BNST），是至关重要的急性阿片类药物戒断的厌恶。这一发现很重要，因为对急性戒断的厌恶是促使成瘾者寻求药物的主要因素，即使在长期禁欲后，这一途径也可能继续发挥作用。这里提出的研究将调查增强偏好和潜在复发的可能机制，包括依赖和戒断后的致敏和焦虑。将研究去甲肾上腺素能信号传导对增强偏好和恢复的可能贡献。这些实验的结果将揭示由依赖引起的大脑长期变化的潜在机制，这些变化增加了长期戒断期间的药物寻求。

DESCRIPTION (provided by applicant): Many drug abusers succeed in becoming drug-free for days to months, but most of these individuals experience persistent cravings and relapse long after acute, physical withdrawal, during a period termed protracted withdrawal. Such results indicate that previous exposure and dependence on a drug causes long-term changes that affect subsequent drug preference and seeking. Recently, our lab found that rats made dependent on morphine via pellet implantation and then withdrawn for 5 weeks showed an enhanced preference for morphine as compared to placebo pellet-implanted animals when tested in a conditioned place preference paradigm. Our lab also found that the ventral noradrenergic bundle, which carries information from medullary noradrenergic neurons to the bed nucleus of the stria terminalis (BNST), is crucial for the aversiveness of acute opiate withdrawal. This finding is important because the aversiveness of acute withdrawal is a primary factor motivating addicts to seek drugs, and this pathway may continue to play a role even after long periods of abstinence. The studies proposed here will investigate possible mechanisms of enhanced preference and potentially relapse, including sensitization and anxiety following dependence and withdrawal. Noradrenergic signaling will be investigated for its possible contributions to enhanced preference and reinstatement. Results from these experiments will reveal mechanisms underlying the long-lasting changes in the brain caused by dependence that increase drug seeking during protracted withdrawal.