Involvement of protracted withdrawl in morphine relapse

描述(由申请人提供)： 许多吸毒者成功地在几天到几个月内戒毒，但这些人中的大多数都经历了持续的渴望，并在急性身体戒断后很长一段时间内复发，这段时间被称为长期戒断。这些结果表明，以前接触和依赖一种药物会导致长期的变化，从而影响随后的药物偏好和寻求。最近，我们的实验室发现，在条件性位置偏好范式中，与植入安慰剂的颗粒植入的动物相比，通过颗粒植入使大鼠对吗啡产生依赖，然后戒断5周，大鼠对吗啡的偏好增强。我们的实验室还发现，腹侧去甲肾上腺素能束将信息从延髓去甲肾上腺素能神经元传递到终纹床核(BNST)，这对急性阿片类药物戒断的厌恶至关重要。这一发现很重要，因为对急性戒断的厌恶是促使吸毒者寻求毒品的主要因素，即使在长期戒断之后，这一途径可能仍会继续发挥作用。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敏感化和焦虑。去甲肾上腺素能信号将被研究其对增强偏好和恢复的可能贡献。这些实验的结果将揭示大脑中长期变化的机制，这些变化是由依赖引起的，这种依赖在长期戒断期间增加了药物寻求。

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 Recently, our lab found that rats made dependent on morphine via pellet implantation and then withdrawn for 5 weeks showed an enhanced preference for morphine as compared to placebo pellet-implanted animals when tested in a conditioned place preference paradigm.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.